User:Biosthmors/Saint Louis University: Signal Transduction (Spring 2013)

This is a course page for the Wikipedia assignment by the Signal Transduction class at Saint Louis University, led by professor User:Biolprof and ambassador User:Biosthmors. The other course page is at Education Program:Saint Louis University/Signal Transduction (SP13).

User names, articles, drafts

1. BreCaitlin (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox
2. MChapman5 (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox
3. Maximus155 (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox
4. Gpruett2 (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox
5. Hakkinen2013 (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox
6. Jnims (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox
7. Flemingrjf (talk · contribs) — Existing article title or planned one (edit | talk | history | protect | delete | links | watch | logs | views) — Sandbox

Instructor & ambassador

1. Biolprof (talk · contribs) & Biosthmors (talk · contribs)

BreCaitlin

I'm editing Wikipedia as part of this assignment and here's a link to my sandbox

Assignment 2

Differences [1] [2] [3]

Assignment 4

Difference [4]

Assignment 6

Differences [5]

Assignment 8

Differences [6]

Welcome

That's definitely not a T-rex. Welcome! Biosthmors (talk) 20:10, 23 January 2013 (UTC)

Good edit. I wondered why it was there! Biosthmors (talk) 18:51, 31 January 2013 (UTC)

No need to add a signature (~~~~) in your WP:Edit summaries. They just go on talk pages, per the WP:Cheatsheet. Best! Biosthmors (talk) 22:05, 31 January 2013 (UTC)

Could you please sign your talk page comment? Thanks! Biosthmors (talk) 01:17, 1 February 2013 (UTC)

SR Proteins

I looked at the links you posted on my Talk page and I agree that this looks like a good topic for you. No need to spend time looking for runner ups when you've got a good topic that is both tied to your research project that fits well with the course assignments. Biolprof (talk) 00:55, 4 February 2013 (UTC)

Please go ahead and add SR protein to the course page as your topic. Here are two more articles that may be helpful and may bring a bit more signaling aspect for your lecture.

• Regulating the regulators. (If you can't access this through SLU's library, I can get it for you or you can get it through interlibrary loan.)
• Regulation by phosphorylation.

Your editing for the WikiProject should not be limited to signal transduction, but your lecture should emphasize that aspect. Let me know if you have any questions.

Side note: if you have not seen the responses to your comment here, you should look at it now. It's nice to see how even minor comments can have lasting effects on WP.

Biolprof (talk) 18:09, 7 February 2013 (UTC)

Help us improve the Wikipedia Education Program

Hi BreCaitlin! As a student editor on Wikipedia, you have a lot of valuable experience about what it's like to edit as a part of a classroom assignment. In order to help other students like you enjoy editing while contributing positively to Wikipedia, it's extremely helpful to hear from real student editors about their challenges, successes, and support needs. Please take a few minutes to answer these questions by clicking below. (Note that the responses are posted to a public wiki page.) Thanks!

Delivered on behalf of User:Sage Ross (WMF), 17:17, 10 April 2013 (UTC)

Diffs

Nice job so far! Please remember to include the diffs on your user page for the next assignment (as descrbed in "What will be graded" for Assignment 2). Many thanks. Biolprof (talk) 03:40, 14 April 2013 (UTC)

Disambiguation link notification for May 8

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File permission problem with File:SR proteins competing with hnRNPs.png

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I'm editing Wikipedia as part of this assignment and here's a link to my sandbox

SR proteins

SR proteins are a conserved family of splicing proteins rich in alternating arginine and serine protein residues. SR proteins are important in constitutive and alternative pre-mRNA splicing and some post splicing activities of mRNA. Proteins are classified as SR proteins if they have at least one RNA recognition motif (RRM) and one RS Domain. Other qualification include recognition by the antibody mAb104 and purification using magnesium chloride. In some cases a protein may lack the RRM domain, but is able to interact with RNA through other means. These proteins are called SR-related proteins. SR proteins are localized to the nucleus of cells, specifically in nuclear speckles.

SR proteins were discovered in the 1990's in Drosophila and around the same time in amphibian oocytes. Further investigation has found SR proteins in humans. In general, metazoans, multicellular organisms, appear to have SR proteins and unicellular organisms lack SR proteins.

SR proteins have RNA recognition sites at N- and C-terminus arginine and serine rich sites.

In plants it is thought that SR proteins play a role in development of specific tissues and responses to stress. SR proteins also have a role in regulating post-splicing mRNA metabolism and general mRNA metabolism.

SR proteins also bind to histone 3 tail to participate in transcriptional elongation to further organize gene expression not only at the RNA level, but also at the DNA level.

References

This concludes BreCaitlin's user, user talk, and sandbox pages.

MChapman5

About me

I'm editing Wikipedia as part of this assignment and here's a link to my sandbox. I am sure this is going to be a great semester to learn about Signal Transduction. Together, let's see what we can accomplish.

Projects

This user is a member of WikiProject Molecular and Cellular Biology.

Assignment 2

Proteasome edits: [7]

Article edits: [8] [9] [10]

Assignment 3

Wiki Article

I will be working on editing the following article over the Spring 2013 semester: Plant Disease Resistance

I will be the Wikipedia editor to:

1. Maximus155
2. BreCaitlin

Assignment 4

Plant disease resistance edits: [11] [12] [13] [14]

Assignment 5

Peer reviewed the article Circulating microvesicle.

Assignment 6

Article edits following reviewer's comments: [15]

Second contribution (editing, wiki-links, image added, sections revised) to article: [16]

Assignment 7

Peer review comments for BreCaitlin: [17]

Opened peer review: Peer review page: SR proteins

Assignment 8

Responses to reviewer's comments: [18]

Article edits following the reviewer's comments: [19]

Peer Review Comments for remaining classmates:

Grace: [20]

Ian: [21]

Julia: [22]

Bobby: [23] [24] [25]

Response to comments from remaining classmates: [26]

Welcome

I'm sure it will be great too. You're off to a great start! Best. Biosthmors (talk) 20:10, 23 January 2013 (UTC)

Thanks! I'm having fun with it so far. Also, I found some topics and posted them in my sandbox, on Biolprof's talk, and also on the Wikiproject Cell Signaling talk page. I haven't had any responses to them yet, but I'm remaining hopeful! Let me know if you get a chance to look over some of the topics. I'd be curious what you think would be a good one to start on. MChapman5 (talk) 18:54, 29 January 2013 (UTC)

MChapman5, you are invited to the Teahouse

Hi MChapman5! Thanks for contributing to Wikipedia. Be our guest at the Teahouse! The Teahouse is a friendly space where new editors can ask questions about contributing to Wikipedia and get help from peers and experienced editors. I hope to see you there! Jtmorgan (I'm a Teahouse host) Visit the Teahouse This message was delivered automatically by your robot friend, HostBot (talk) 01:15, 24 January 2013 (UTC)

Talkback

Hello, Biosthmors. You have new messages at Talk:Proteasome.
Message added 03:05, 4 February 2013 (UTC). You can remove this notice at any time by removing the {{Talkback}} or {{Tb}} template.

§everal⇒|Times 03:05, 4 February 2013 (UTC)

Help us improve the Wikipedia Education Program

Hi MChapman5! As a student editor on Wikipedia, you have a lot of valuable experience about what it's like to edit as a part of a classroom assignment. In order to help other students like you enjoy editing while contributing positively to Wikipedia, it's extremely helpful to hear from real student editors about their challenges, successes, and support needs. Please take a few minutes to answer these questions by clicking below. (Note that the responses are posted to a public wiki page.) Thanks!

Delivered on behalf of User:Sage Ross (WMF), 16:31, 10 April 2013 (UTC)

Sorry about that

I hope you were the first in the class to notice the issue you identified at Education Program talk:Saint Louis University/Signal Transduction (SP13). It should be fixed now. Thanks. Biosthmors (talk) 09:05, 20 April 2013 (UTC)

Project/Lecture in BIOL 512

Signal Transduction of Ubiquitin in Plant Immunity

Project article page: Plant Disease Resistance

Mechanism of action

Ubiquitination is a central role in cell signaling that regulates several processes including protein degradation and immunological response. Much of the defense in plants relies on the destruction of defective or invaded materials within the cell, increasing the importance of functional proteasomes and protein targeting. Although one of the main functions of ubiquitin is to target proteins for destruction, it is also useful in signaling pathways, hormone release, apoptosis, and translocation of materials throughout the cell. Even in plants, ubiquitination is a key factor in several immune responses that are vital for the organism's survival. Without ubiquitin's proper functioning, the invasion of pathogens and other harmful molecules would increase dramatically due to weakened defenses in the plant's immunity.

The E3 Ubiquitin ligase enzyme is the main component that provides specificity in the regulation of immune signaling pathways. The E3 enzymes components are determined by which domains they contain and range from several types. These include the Ring and U-box single subunit, HECT, and CRLs. These plant signaling pathways are controlled by several feedback pathways, mainly negative feedback pathways; and they are regulated by De-ubiquitination enzymes, degradation of transcription factors, and the activation of transcription factors.

Types of plant immunity

Plants contain two branches of immunity that differ from the immunity that are present in most animals. The first branch of immunity is called PAMP-Triggered Immunity (PTI) and is the first inducible response performed by plants. It is activated by PAMPS, such as flagellin, toxins, or LPS, and it usually halts the production of pathogenic genes. This is most commonly achieved through the use of Reactive Oxygen Species (ROS) or by reinforcement of the cell wall. This production is the result of the activation of the MAPK Pathway as well as the production and use of hormones.

The second branch of plant immunity is known as Effector Triggered Immunity (ETI) and is activated by the presence of pathogenic effectors. ETI causes a hypersensitive cell death response and an increase in programmed cell death. This process is regulated by nitric oxide production, SA accumulation, potassium, protons, and intracellular calcium pathways.

Transcription factors and the hormone response

Much of a plant's activity is regulated by signaling hormones such as:

• Salicylic acid (growth, development, transportation)
• Jasmonic acid (response to stresses, growth inhibition, flower development)
• Ethylene (growth regulation, signaling, etc.)

Signaling messages can also be regulated by ion signaling, degradation, or negative feedback. The transcription responses from these factors usually induce a primary gene response, which triggers a secondary gene response, and finally the cross-talk interaction of the two causes a system acquired response (SAR) in the plant. These responses are thought to be regulated by transcription pulses, which may be caused by a change in redox reactions that dictate these pulses within 24-48 hour spans. These pulses are mutually exclusive within a single cell, allowing transcription factors to be activated before inducing the SAR.

A majority of the plant's gene expression in the immunological response is regulated by degradation. This degradation can occur by either conformational changes, enhancers, or repressors of various hormones. Some examples of these hormones are:

• Auxin: binds to target repressor for degradation
• Jasmonic Acid: leads to degradation of JAZ
• Gibberellic Acid: Conformational change binds Della and targets with E3 for degradation
• Ethylene: protects regulators by degrading E3 components by an unknown E3

Signaling

E3 Signaling

E3 ubiquitin ligases have various roles in the ubiquitin pathway for immune signaling, which include plant defenses. The E3 role in ubiquitination and signaling is of major importance in the immune response, and the primary functioning of the enzymes include the following:

• Regulators of hypersensitive cell death
• Regulators of plant resistance
• Regulators of PAMP (PAMP-Triggered Immunity)
• Regulators of SAR (System Acquired Response)
• Regulators of transcription factors
• Regulators of hormone response

Receptor-like kinase

The receptors found in plants are of similar structure to those of vertebrates and other organisms. These receptor-like kinases function in a similar way to the Receptor tyrosine kinases and partake in various enzymatic activity. The majority of the kinases involve ubiquitin ligase and culminate in the degradation of proteins. Most of the kinase pathways are activated and regulated by the presence of R proteins, phosphorylation, negative regulation, or various mechanisms that are still unknown.

Signaling pathways in innate immunity

Structure and receptor function are conserved among species such as Drosophila, mammals, and even plants. There are some differences in binding proteins and signaling pathways, but they regulate similar endpoints, with a majority of the endpoints being the MAP Kinase Pathway. The signaling for innate immunity in plants is controlled mostly by leucine-rich repeat (LRR) receptors, and it is this receptor that activates the transcription factors via the MAPK Pathway, which activates the plant's immune responses.

References

This concludes MChapman5's user, user talk, and sandbox pages.

Maximus155

I'm editing Wikipedia as part of this assignment and here's a link to my sandbox.

I will be creating and editing articles related to the Signal Transduction, a topic in Biology.

Category:Signal transduction

Assignment 6 diffs http://en.wikipedia.org/w/index.php?title=Circulating_microvesicle&diff=550591216&oldid=550508925

Assignment 8 diffs http://en.wikipedia.org/w/index.php?title=Circulating_microvesicle&diff=554674329&oldid=554452663

Welcome

I said hello to the world on your sandbox, like you asked. Welcome! Biosthmors (talk) 20:25, 23 January 2013 (UTC)

Help us improve the Wikipedia Education Program

Hi Maximus155! As a student editor on Wikipedia, you have a lot of valuable experience about what it's like to edit as a part of a classroom assignment. In order to help other students like you enjoy editing while contributing positively to Wikipedia, it's extremely helpful to hear from real student editors about their challenges, successes, and support needs. Please take a few minutes to answer these questions by clicking below. (Note that the responses are posted to a public wiki page.) Thanks!

Delivered on behalf of User:Sage Ross (WMF), 16:57, 10 April 2013 (UTC)

WP assignment

Please add the template from Assignment #3 to the Talk:Circulating microvesicle page. Also, please include the diffs on your user page for the next assignment (as descrbed in "What will be graded" for Assignment 2). Thanks. Biolprof (talk) 23:47, 13 April 2013 (UTC)

I was curious about references 2 and 3, which at cMVs currently have errors listed instead of sources. Best. Biosthmors (talk) 01:27, 12 May 2013 (UTC)

Thanks for picking that up. I was making some edits and I must have made some mistakes. It has been fixed. Maximus155 (talk) 01:49, 12 May 2013 (UTC)

Mchapman5 Peer review

Article summary

• I notice that there are a few opportunities for wikipedia links in the summary. Many of the bolded words could be wiki links, or at least red links to indicate that there should be an article about them, e.g. disease triangle.
• Perhaps elaborate more on pre-formed defenses and infection induced responses here.
• Needs some citations for facts that aren't actually stated in the article, e.g. crop loss due to diseases.

Common mechanisms for disease resistance

• I'm sure you were already planning on doing this, but it is a good idea to elaborate on some of these bullets. Not only just giving examples of certain mechanisms, but also explaining how they act to protect the plant.
• Wiki links as well as citations would be good for this section
• Is it typical to utilize piped wiki links as you do? 'Plants' roots release chemicals that attract beneficial bacteria to fight off infections' links to 'Plant use of endophytic fungi in defense' and I'm not sure its appropriate to have large sections of text form a link.

Plant immune systems

• it says that plant immunity has a common origin as insects and mammals, I don't think this is true. Multicellularity evolved independently after the plant lineage branched off of the rest of the eukaryotes. If this is true then there needs to be a citation.
• You say that plant immunity is different than in animals, but then say plants can sense pathogens. That is a little misleading since animals immune systems can detect pathogens as well. I think the point you are trying to make here is that there is a difference in the mechanism that plants use to detect pathogens.
• In this sections header you say, 'as described below'. I'm not sure that is appropriate wikipedia prose.
• In this sections header you talk about PTIs and ETIs, but the section also includes two other subsections that aren't covered in the header(RNA interference and Defense against whole pathogen species). It would be nice if you could elegantly fit them in as well.
• Lots of opportunities again for wiki links

PAMP triggered immunity

• You implied earlier that PAMPs and MAMPs were synonyms, but this section seems to indicate that there is a distinction. Could you elaborate?
• Would it be better to include more information about what types of responses are activated in the PTI response
• Last sentence seems like it is a bridge between the PTI section and the ETI section. It might be more appropriate to put it at the beginning of the ETI section instead, since it indicates the importance of the ETI in catching pathogens that get past the PTI.
• No citations after the first sentence.

Effector triggered immunity

• This section is much more complete than the PAMP triggered immunity section.
• 'see below' is probably not necessary.
• What is an effector? Moving the last sentence of the PTI section to the ETI section would fix this.
• When you list NB-LLR protein names you finish the list with 'and other acronyms'. If there are too many names to reasonably list, then maybe 'among other names' would be a better way to finish it.
• Are virulence factors the same as effectors?
• Are avirulence genes the same as R genes?
• You later say pathogen avirulence genes, do you mean virulence genes. Virulent means highly infective and I would assume avirulent means the opposite.
• I don't know if I would considered plant pathogen interactions to be a signaling pathway. Possibly rephrase that sentence. Look up Red queen hypothesis
• It may be important to talk about symbiotic organisms that interact with plants e.g. legumes and nitrogen fixing bacteria or bacteria within the rhizosphere. These organisms need a mechanism(effectors?) to get around the plants defenses. In these cases the organism would not be considered a pathogen.

RNA interference

• How does infected cells signaling to uninfected cells improve their resistance? Does it improve or up regulate the RISC pathway? The systemic acquired resistance page doesn't say anything about RISC so the signaling pathway and systemic acquired resistance may not be appropriate for this section.
• Are there specific viruses that are affected by RNAi? viruses with dsRNA genomes are obvious targets, but are other types of viruses inhibited by the pathway.
• You say it is the result of prior infections, is viral RNA stored within the cell? Does the RNA get transferred in some way to other cells in the plant? Please elaborate on this point.

Defense against whole pathogen species

• Is there a term used to describe this suite of defense mechanisms or is it just called 'defense against whole pathogen species?'
• You talk about specific genes that are extremely effective against whole species of pathogens. When these genes are knocked out do they lose resistance? If another species is transformed with these genes does it become resistant? The reason I ask is how is it known that these genes alone are responsible for this resistance?
• Does inability to colonize a host mean that the host is not habitable for the bacteria? I'm not sure if that would even fall under plant immunity.
• Does pre-formed defenses include chemicals that inhibit growth? Plants produce a lot of phytochemicals, many of which may be anti-microbial. I think this may be a good topic to cover.

Plant disease resistance signaling mechanisms

• The title of this section is kind of a mouthful :)
• You should add a section summary

Transcription factors and the hormone response

• I feel like the summary could probably be a little more detailed
• Maybe it should just be the hormone response.

Mechanism of transcription factors and hormones

• Signaling as a role of ethylene is a little redundant
• It may be better to talk about the roles of plant hormones specifically in terms of plant defense instead of their other roles.

Regulation by degradation

• I'm a little confused by what is being degraded. Are you talking about the hormones being degraded or their interacting proteins?

Receptor-like kinase

• First sentence is really long. Maybe split it up into two or more sentences
• How are RLKs activated and regulated by these things? Wouldn't the pathogen itself bind to the RLK and activate it?

Signaling pathway in innate immunity

• How is this different from the RLK section? I didn't think plants had a robust adaptive immunity besides the RNAi.

Ubiquitin and E3 signaling

• I wouldn't say 'even in plants' since the article is supposed to be about plants.
• Your list could use a little more elaboration.

Plant breeding and disease resistance

• No citations in this section
• You say that diseases can be controlled by pesticides, but didn't you say herbivory was a different thing? Does it prevent insects from allowing infections to occur?
• Genetic modification is a good source of plant resistance. You talk about it later but it probably belongs in the list.
• You say that there are many exceptions to vertical and horizontal resistance but don't give any.

Host range

• citations
• It would be nice to have specific examples of horizontal gene transfer and the development of toxins to become pathogenic.

Epidemics and population biology

• I like this section, but maybe it should be included in the Plant breeding for disease resistance section.

References

This concludes Maximus155's user, user talk, and sandbox pages.

Gpruett2

About Me

I'm editing Wikipedia as part of this assignment and here's a link to my sandbox

Education Program:Saint Louis University/Signal Transduction

Assignment 2

Proteasome Edit: [27]

Article Edits: [28] [29] [30]

Assignment 3

I will be editing the following article: Wnt signaling pathway

Assignment 4

First Contribution: [31]

Assignment 5

Second Contribution: [32]

Assignment 8

Final Contributions: [33], [34], [35], [36], [37]

Welcome

Welcome! I'm curious. How did you develop the citation in your sandbox? I used [38] and came out with: Ben-Shlomo I, Yu Hsu S, Rauch R, Kowalski HW, Hsueh AJ (2003). "Signaling receptome: a genomic and evolutionary perspective of plasma membrane receptors involved in signal transduction". Sci. STKE. 2003 (187): RE9. doi:10.1126/stke.2003.187.re9. PMID 12815191. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Best! Biosthmors (talk) 20:28, 23 January 2013 (UTC)

Also, access dates are only helpful for website references (in case it changes or goes dead). Since it's a journal, no need. Best! Biosthmors (talk) 20:30, 23 January 2013 (UTC)

Topic for Course Assignment-

There is already quite a bit of info in the Wnt signaling pathway article, but you have already identified ways that it needs to be improved on the talk page and it is an important topic with lots more that could be added and/or clarified. There is plenty on that topic for your lecture as well, so unless you are leaning toward something else, I think that would be a very good choice. Biolprof (talk) 21:13, 7 February 2013 (UTC)

Assignment 3 copy editing

I made some changes for you to review, but I don't think I have any suggestions that I didn't already implement. Jnims (talk) 23:21, 18 February 2013 (UTC)

Ian's Fact Checking

I think a lot of what you have is good, since it is so "well understood" at this point. I do think I would add a few citations to your work, in particular the last line of "In fact, protein homology suggests that Wnt signaling may have been present in the common ancestor of all bilaterian life." I was searching in your references and on google and could not find something about this. There was a vague reference in your Three Decades citation but not clearly stated. Hakkinen2013 (talk) 04:12, 19 February 2013 (UTC)

Bobby's Fact Checking

Going with Ian said, maybe a few more citations. The sentences seemed to be longer (for better or worse, not my area) to that reduced the need for citations, as one at the end of every sentence seems to be the norm. However, there was a sentence regarding the canonical pathway and non-canonical pathway that seemed to perhaps require a citation. Flemingrjf (talk) 05:30, 19 February 2013 (UTC)

Help us improve the Wikipedia Education Program

Hi Gpruett2! As a student editor on Wikipedia, you have a lot of valuable experience about what it's like to edit as a part of a classroom assignment. In order to help other students like you enjoy editing while contributing positively to Wikipedia, it's extremely helpful to hear from real student editors about their challenges, successes, and support needs. Please take a few minutes to answer these questions by clicking below. (Note that the responses are posted to a public wiki page.) Thanks!

Delivered on behalf of User:Sage Ross (WMF), 16:56, 10 April 2013 (UTC)

Assignment 7

Overall some nice additions to the wikipedia article.

Intro: I think that your change from Breast Cancer to saying Just cancer was not needed. The way it was before was more specific.

Discovery: Very clear and a good insight into why it is called Wnt. Those Drosophila people get all the credit!

Wnt Signaling proteins: I think you can link the X. laevis (african clawed frog) and D. melanogaster in the table.

Mechanisms: When you mention FZ being a GPCR you do not need to say "thus it spans the membrane 7x"

Your figures look great! Publishable quality! — Preceding unsigned comment added by Hakkinen2013 (talk • contribs) 18:09, 22 April 2013 (UTC)

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Barnstar

		The Excellent New Editor's Barnstar A new editor on the right path
		Thanks for all your contributions on Wnt signalling pathway! Most recently, I just noticed your copy-edits to improve the wording. Nice job on the article! Biosthmors (talk) 23:28, 11 May 2013 (UTC)

Good job on responding to the comments. Unfortunately sometimes one can face withering criticism on this website as a beginner. It drives many away. But I applaud your determination to continue to improve the article so that readers are served better. That's fantastic. Thank you very much. Let me know if you have any questions. Biosthmors (talk) 17:46, 14 May 2013 (UTC)

Thanks

Thanks for the edits! I'll see if I can leave you some more comments shortly. Also, if you want to see who has been active lately at Wikipedia:PRV#Natural_sciences, you might just leave 2 or 3 of them the request to leave some feedback for you on the talk page. You can let them know I sent you over there from the PRV list. Thanks again! Biosthmors (talk) 13:28, 12 September 2013 (UTC)

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Mechanism

Foundation of Wnt signaling

Wnt signaling involves a diverse family of Wnt glycoproteins that act as ligands to regulate the production of intracellular signaling molecules to produce a cellular response. These ligands include several different proteins such as WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16, which are all found in humans. These proteins are commonly associated with embryonic development and oncogenesis.

All Wnt signaling usually begins when one of these proteins binds the N-terminal extra-cellular cysteine-rich domain of a Frizzled (Fz) family receptor. This receptor spans the plasma membrane seven times, which means that it belongs to a family of G protein coupled receptors. However, to facilitate Wnt signaling, co-receptors are also required alongside the interaction between the Wnt protein and Fz receptor. Examples include lipoprotein receptor-related protein (LRP)-5/6, receptor tyrosine kinase (Ryk), and ROR2. Upon activation of the receptor and co-receptors, a signal is sent to either the phosphoprotein Dishevelled (Dsh) or a heterotrimeric G protein, both of which are located in the cytoplasm. If Dsh is used, this signal is transmitted via a direct interaction between Fz and Dsh. In mammals, there are three types of Dsh proteins (Dsh-1, Dish-2, and Dish-3); however, different Dsh are also present in all organisms.(new source) In fact, they all share the following highly conserved protein domains: an amino-terminal DIX domain, a central PDZ domain, and a carboxy-terminal DEP domain. These different domains are important because after Dsh, the Wnt signal can branch off into one of two different pathways and each pathway interacts with a different combination of the three domains.(new source) Likewise, if the heterotrimeric G protein is used, an entirely different pathway is activated.

Canonical and noncanonical pathways

The three main Wnt signaling pathways are the canonical Wnt pathway, the noncanonical Planar Cell Polarity pathway, and the noncanonical Wnt/Ca2+ pathway. As their names suggest, these pathways belong to one of two categories: canonical or noncanonical. The difference between these two categories is the presence or absence of β-catenin. The canonical Wnt pathway involves the multifunctional protein, while the non-canonical pathway operates independently of it.

The canonical Wnt pathway

The ‘’’canonical Wnt pathway’’’ is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family. Without Wnt signaling, the β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it. This destruction complex includes the following proteins: Axin, adenomatosis polyposis coli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α). It degrades β-catenin by targeting it for ubiquitination, which subsequently sends it to the proteasome to be digested. However, as soon as Wnt binds Fz and LRP-5/6, the destruction complex function becomes disrupted. This is due to Wnt causing the translocation of both a negative regulator of Axin and the destruction complex to the plasma membrane. This negative regulator becomes localized to the cytoplasmic tail of LRP-5/6. Phosphorylation by other proteins in the destruction complex subsequently binds Axin to this tail as well. Axin becomes de-phosphorylated and its stability and levels are decreased. Dsh then becomes activated via phosphorylation and its DIX and PDZ domains inhibit the GSK3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF transcription factors.

The noncanonical Planar Cell Polarity pathway

The ‘’’noncanonical Planar Cell Polarity (PCP) pathway’’’ is one of the two Wnt pathways that does not involve β-catenin. It does not use LRP-5/6 as its co-receptor and is thought to use NRH1, Ryk, PTK7, or ROR2. As in the canonical Wnt pathway, the PCP pathway is activated via the binding of Wnt to Fz and its co-receptor. The receptor then recruits Dsh, which uses its PDZ and DEP domains to form a complex with Dishevelled associated activator of morphogenesis 1 (DAAM1). Daam1 then activates the small G-protein Rho through a guanine exchange factor. Rho activates Rho-associated kinase (ROCK), which is one of the major regulators of the cytoskeleton. Dsh also forms a complex with rac1 and mediates profilin binding to actin. Rac1 activates JNK and can also lead to actin polymerization. Profilin binding to actin can result in restructuring of the cytoskeleton and gastrulation.

The noncanonical Wnt/calcium pathway

In the ‘’’Wnt/calcium pathway’’’, Wnt5a and Frizzled regulate intracellular calcium levels. Ligand binding causes the coupled G-protein to activate PLC, leading to the generation of DAG and IP3. When IP3 binds to its receptor on the ER, intracellular calcium concentration increase. Ligand binding also activates cGMP-specific phosphodiesterase (PDE), which depletes cGMP and further increases calcium concentration. Increased concentrations of calcium and DAG can activate Cdc42 (cell division control protein 42) through PKC. Cdc42 is an important regulator of cell adhesion, migration, and tissue separation.[24] Increased calcium also activates calcineurin and CaMKII (calcium/calmodulin-dependent kinase). Calcineurin induces activation of transcription factor NFAT, which regulates ventral patterning. CamKII activates TAK1 and NLK kinase, which can interfere with TCF/ß-Catenin signaling in the canonical pathway. ref name="Sugimura">Sugimura, Ryohichi, and Linheng Li. "Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases." Birth Defects Research Part C: Embryo Today: Reviews 90.4 (2010) : 243-256. Print.</ref>

Other pathways

The canonical, PCP, and Wnt/Calcium pathways are the most well known and best studied of the Wnt pathways, but they are not the only ones and new pathways are beginning to surface. In the ‘’’Wnt/GSK3 pathway’’’, Wnt inhibition of GSK-3 activates mTOR without involvement of β-Catenin, such that rapamycin can inhibit Wnt-induced cell growth and cancer formation.

Future references

• Dimeo, Theresa A.; Anderson, Kristen; Phadke, Pushkar; Feng, Chang; Perou, Charles M.; Naber, Steven; Kuperwasser, Charlotte (1 July 2009). "A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer". Cancer Research. 69 (13): 5364–5373. doi:10.1158/0008-5472.CAN-08-4135. PMC 2782448. PMID 19549913.
• Gilbert, Scott F. (2010). Developmental biology (9th ed.). Sunderland, Mass.: Sinauer Associates. ISBN 9780878933846.
• Laskus, T (1989 Jun). "[Delta infection in various forms of hepatitis B]". Polskie Archiwum Medycyny Wewnetrznej. 81 (6): 330–5. PMID PMC2634250. {{cite journal}}: Check |pmid= value (help); Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)</ref>

References/Bibliography

Gpruett2 (talk) 07:05, 13 February 2013 (UTC)

This concludes Gpruett2's user, user talk, and sandbox pages.

Hakkinen2013

"I'm editing Wikipedia as part of this assignment and here's a link to my sandbox."

Welcome

I hope you get in and off the wait list. =) I'm your online ambassador. Since you're interested in medical stuff, check out the discussion at WT:MED. Best! Biosthmors (talk) 20:01, 23 January 2013 (UTC)

Also those quotes on your user page are unnecessary. ;-) Biosthmors (talk) 20:01, 23 January 2013 (UTC)

Nice to meet you Biosthmors!Thanks for the link! I wish I had more time, but with work at the Wash U. and this being my first semester back in classes in two years I have had sorta a slow start to getting back in the swing of things.

I will say that I am looking forward to this Wikipedia project for class and always have been curious about the many ways to utilize wikipedia. To say the least I am in a state of awe at this moment with it.

With all the time constraints in my current life I am sure that I will be asking you many questions and for feedback about my noobish early edits/additions.

I try to make very dry jokes at every opportunity hence the strangeness that is my current self page. "Don't be surprised if you see more."

-Hakkinen2013 11:30 on 12313

Nice to meet you too! You're welcome. I'm glad you're looking forward to editing! Please feel free to ask me for help anytime at my talk page. The help desk and Teahouse are also available for you. Just type "WP:" in front of help desk or teahouse to get to either of those two places in the Wikipedia search bar. Sounds good! =) Ah, and also see WP:CHEAT for how to sign talk pages. There's a way to do it with one click too, right above the edit summary box when you click edit. Best! Biosthmors (talk) 21:53, 28 January 2013 (UTC)

Your recent edits

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Assignment 3 copy editing

The following are some of my thoughts and suggestions as your copy editrix:

• Something I didn't want to go ahead and delete without consulting you: Do you need to specify "in vitro cells" in the last sentence of the Signaling section, or is that a bit redundant?

• Also, I reworded the sentence about Adhesion GPCR naming (sentence #2 in "Ligand" section) and wanted to run it by you so you could decide if you want to change it: "Adhesion GPCRs are named for the adhesion-like domains, such as EGF, located on their N-terminus."

• Additionally, is "orphaned" the preferred terminology for describing the status of the Adhesion GPCRs?

• Lastly: Be consistent with capitalization! It looks like "Adhesion GPCR" is the preferred style, so be sure to stick with that.

Jnims (talk) 21:50, 18 February 2013 (UTC)

Assignment 3

Everything looks good so far! — Preceding unsigned comment added by Flemingrjf (talk • contribs) 05:32, 19 February 2013 (UTC)

Assignment 3 copy editing

I noticed in your citing that you have the same reference cited multiple times as many different numbers. In order to have one reference per number, use the following format: < ref name=first author's last name> citation <ref/ > and then < ref name=author's last name/ > to cite again. If you want an example of this, I have it in my article edit in my sandbox. Gpruett2 (talk) 04:10, 21 February 2013 (UTC)

Assignment 5 Peer Review

This first part will be in regards to the entire article as a whole, and then what you have edited. I didn't want to change anything without your thinking it over first, so most of the major things, I will tell you about. The minor ones I went to go in and fix.

• The first thing I noticed was the structure of the article didn't seem to be the best. There is a template about cell signaling pathways that begins with the history/discovery, then the mechanism, then the role, then the human diseases, associated with that structure or pathway, and then the research that is currently being performed on the structure and mechanism. Hopefully this will be a good place to begin. It worked very well for my topic.

• Also that list of human adhesion proteins seems like it is sort of in the way and doesn't provide much to the overall article. Maybe putting it towards the end of the article would be good, as a source where people can go and check on one of the many adhesion proteins.

• There were many places that I felt citations should be made. I was originally going to go through sentence by sentence where I felt there should be citations, but I feel like you know where they should be made. The entire section regarding cleavage had only a couple citations that I felt were not necessary. I completely redid that paragraph as will become apparent later.

• I also moved some citations from the beginning of paragraphs to the end of them, as the one citation was referring to the entire paragraph and not just the first sentence.

• For the first paragraph under signaling, you indicate a technique used for the identification of molecules interacting with the GPCR. However, I feel like citing this technique with a paper that used the technique would be beneficial for people to see how it was done.

• I added citations towards the ends of the paragraphs about the two adhesion proteins listed in the third and fourth paragraphs. I also have an idea that would dramatically change the structure that I will talk about a little bit further on.

• The cleavage section needed a whole overhaul of the language that was used. I felt it was much to confusing and complex for many reasons. I have tried to make it so that a causal viewer can come upon the page and read it with good understanding. If a more advanced person wants knowledge, I feel that that is when they should go to the citations. Also, there were only three citations in this entire section and they all referred to other organisms where the GAIN domain is found. I thought this sentence to be pretty useless and have taken it out, among many other words that I felt were unnecessary. If you don't like the change, feel free and put it back the way it was. I feel that this is more of the style that Wikipedia is going after, however. I didn't want to go in and change everything about the article, but I wanted to provide this as an example for how it should be done I feel. The page is yours, however, so feel free to make the changes you feel should be made. I am just providing that as an example.

• The section on the immune system I found to be very hard to read. As someone with some background knowledge regarding biology at this level, I still found it very difficult to read through.

• The sentence regarding the BAI1 adhesion protein, I redid as well. I thought that by stating what the protein was thought to be involved in and then stating what it actually is involved in was too similar to the review article this came from. It also, at least for me, adds nothing to my knowledge and current understanding about the protein if it is listed about what the protein was thought to have been involved in.

• I liked the way the GPCR adhesion protein GPR126 was described in the Neuronal Development section. I liked that it had multiple citations, and the way the information on this page was written was not anywhere similar to the way that it was presented in the articles that cited it. I thought that was very well done.

• I didn't like the way that GPR56 was addressed in the entire article. Little pieces of it are found everywhere. A paragraph is devoted to it in the ligand section. There is a sentence about it in the immune system section, a sentence about it in the bone marrow section, and a sentence about it in the bilateral frontoparietal polymicrogyria section. This brings me to a main point that I had regarding the article as a whole. I feel that a much better structure for this article were to describe each GPCR adhesion protein as if it were its own perhaps mini article, where the ligands, signaling, functional roles, and roles in disease were all put into one section that was all under the heading of the GPR56. Perhaps a better method would be to even put most of this information in the GPR56 page of wikipedia. I also noticed with the GPR12 protein, there was more information on the GPCR adhesion protein in this article than there was on the actual GPR12 article itself. It might be hard to figure out where the information should go, especially if you are trying to fix the main article, regarding ahesion GPCRs. I went searching on Pubmed for general review articles about adhesion GPCRs and found several that seemed to be very good places to begin, as a sort of overview of the GPCR adhesion proteins in general. It seemed like many of the articles that you have cited are primary articles, that could be very dense and hard to get through, while coming to a conclusion that yields the same knowledge that one sentence of a review article could provide. Those primary articles also seem to focus in on one mechanism or structure of one GPCR adhesion protein without addressing what you want to be addressing, which is the overall view of GPCR adhesion proteins.

• This leads me to another very important point, which is that the way you cited the articles, one on Wikipedia is not simply able to follow the link to a website such as Pubmed. I have included where you can use citations for the Pubmed journal articles Wikipedia template filling tool. I will do a couple for you. When doing this, you need to make sure you press the "Add ref tag" button below. I think it is very important to make them so you are able to follow the link to the article online. I feel that this is very important for someone who is doing some research of their own and have gone to Wikipedia as a starting place. In the past, I have gone to a Wikipedia page to mainly look for articles that were cited at the bottom of the page and not pay heed to the information that was presented at the top.

• Here are a few more things about the citations, upon which I clicked on and delved into the article a bit. In the second paragraph of signaling, regarding the GPR133 protein, the wording you used and the wording that was used in the research article is very similar, except where you use "via" they use the word "through."

• For the the citation regarding the Lat-1 protein, I felt that the sentence summed up the article very well without directly copying any of their specific word usage. I thought that this was very well done. I thought that the paragraph was a little wordy as well. I feel like you could simply state that the GPS domain and the 7 transmembrane domain are required for the Lat-1 signaling. In addition, I was not convinced after going into the article that the GPS site was necessary as part of an endogenous ligand. But you have probably read it more clearly than I have. In addition, when you link to the GPS, it gives you the Global Positioning System page, and not the GPS you are talking about.

• For the citation and the overall entry about the bone marrow GPCR adhesion protein, I felt that taking one sentence from the primary literature on one GPCR adhesion protein and using that as part of a section on the Wikipedia entry of all of the GPCR adhesion proteins may not be the best way to style the article. I also made the sentence more concise.

Flemingrjf (talk) 07:56, 25 March 2013 (UTC)

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Hello

Hey there how's your assignment going? I was looking at that and I thought "have been shown to" could be removed (copy-edited out). Also, if this is a tentative report ("possibly interact") then is it worth mentioning? Might we be better off to wait on a secondary source (if it is based on one primary report) lest it is contradicted soon? I'm not knowledgeable on the literature. Just some thoughts! I hope you're doing well. Best. Biosthmors (talk) 12:53, 21 April 2013 (UTC)

My apologies

I see that you put Wikipedia:Peer review/Mammalian target of rapamycin/archive1 up but because I didn't see a link in the second box of the course page section here, I didn't see it to comment before it closed. I'm sorry about that! Best. Biosthmors (talk) 20:01, 16 May 2013 (UTC)

Assignment 1

I just got wait listed for medical school and in other news...

cAMP is an amazing second messenger necessary for myelination in Mouse Schwann cells

tg(Foxd3:18gfp) Zebrafish Larvae 30hpf Schwann cell precursors can be seen migrating down the posterior lateral line nerve. The leading Schwann cell can be seen extending processes outward.

Assignment 2

Proteasome

"The proteasome most exclusively used in mammals is the cytosolic 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass containing one 20S protein subunit and two 19S regulatory cap subunits." I would like to edit this to be...

The proteasome most exclusively used in mammals and found "exclusively in Eukaryotes" is the cytosolic 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass containing one 20S protein subunit and two 19S regulatory cap subunits.

The talk page as had a section added about the S26 proteasome Talk:Proteasome

Links to my three page edits and comments Adhesion-GPCRs , Talk:ErbB , Talk:EGR1

here is a link to my edit for Adhesion-GPCRs [39] and ErbB 2 and finally EGR1 3

Link to my added info for Wikipedia talk:WikiProject Cell Signaling

Link to my added info for User talk:Biolprof

Assignment 3

I will be mock adding to two headings in the Adhesion-GPCRs page. The two headings are ligand and signaling.

Ligand A majority of the Adhesion GPCRs are orphan receptors and work is currently underway to de-orphanize as many of these receptors as possible. Adhesion GPCRs get their name from their N-terminal domains that have adhesion-like domains, such as EGF. While ligands for many receptors are still not known, researchers are utilizing drug libraries to investigate compounds that can activate GPCRs and using these data for future ligand research.

Signaling Adhesion GPCRs follow standard GPCR signaling and signal through Gαs, Gαq, Gαi, and Gα12/13. As of today, many of the 800 Adhesion GPCRs are still orphan receptors and their signalling pathways are also not identified. Research groups are working to elucidate the downstream signaling molecules utilizing several methods, including chemical screens and analysis of second messenger levels in over-expressed cells. Adding drugs in vitro, while the cells are over-expressing an Adhesion GPCR has allowed the identification of which molecules are activating the GPCR and the second messenger it is utilizing.

I am trying to figure out a way to cite a source only once and then reuse the citation number over instead of it becoming a new citation each time.

I believe you just reuse the ref tags from the previous citation (so that they're exactly the same) and it will show up under the same number. Maybe also ask Grace, as she is our group's Wikipedia point person.

got it thanks!

All comment changes considered and changed. Thanks for all the suggestions.

Assignment 4

Evolution of Adhesion GPCRs: Adhesion GPCRs are found in Fungi. It is believed that Adhesion GPCRs evolved from the cAMP receptor family and arose approximately 1275 million years ago, before the split of Unikots from a common ancestor. Several Fungi have novel adhesion GPCRs that have both short, 2-66 amino acid residues, and long, 312-4202 amino acid residues. Analysis of Fungi showed that there were no secretin receptor family GPCRs, which suggests that they evolved from Adhesion GPCRs in a later organism.

Genome analysis of the TeleostFugu has revealed that it has only two adhesion GPCRs that showed homology to Ig-hepta/GPR116. While the Fugu genome is relatively compact and limited with the number of adhesion GPCRs, the Tetraodon nigroviridis another species of puffer fish has considerably more, 29 adhesion GPCRs.

Ligands Adhesion GPCRs have numerous orphan receptors and many groups as of 2013 are working to de-orphanize them. One GPCR, GPR56, currently has a known ligand, Collagen III, which is involved in neural migration inhibition. GPR56 has been shown to be the cause of polymicrogyria in humans and may play a role in cancer metastasis. The binding of Collagen III to GPR56 occurs on the N-terminus and has been narrowed down to a short stretch of aminoacids. The N-terminus of GPR56 is naturally glycosylated, but this glycosylation is not necessary for Collagen III binding. Collagen III, results in GPR56 to signal through Gα12/13 activating RhoA.

Role in disease: BFPP Mutations in GPR56 result in bilateral frontoparietal polymicrogyria in humans, characterized by abnormal neuronal migration and surface ectopias.

Signaling Adhesion GPCRs follow standard GPCR signaling and signal through Gαs, Gαq, Gαi, and Gα12/13. As of today, many of the 800 Adhesion GPCRs are still orphan receptors and their signalling pathways are also not identified. Research groups are working to elucidate the downstream signaling molecules utilizing several methods, including chemical screens and analysis of second messenger levels in over-expressed cells. Adding drugs in vitro, while the cells are over-expressing an Adhesion GPCR has allowed the identification of which molecules are activating the GPCR and the second messenger it is utilizing.

GPR133 signals through Gαs to activate adenylyl cyclase. It has been shown that overexpressing GPCRs in vitro leads can result in receptor activation in absence of ligand or agonist. By over expressing GPR133 in vitro and an elevation in reporter genes and cAMP was observed. Signaling of the overexpressed GPR133 did not require an N-terminus, nor was GPS cleavage. Missense mutations in the 7tm resulted in loss of signalling.

Lat-1 was shown in C. elegans to require a GPS for signaling, but cleavage at the GPS site was not. Having a shortened 7 transmembrane domain, but an intact GPS domain also resulted in a loss of signaling, suggesting that the two are involved in signaling together and that the GPS site could act as an endogenous ligand.

Bone marrow and hematapoietic stem cells

GPR56 knockout mice have a decreased number of hematopoietic stem cell in the bone marrow, while higher levels were found in the spleen and peripheral blood. This suggest that GPR56 plays a role in interactions between bone marrow and hematapoietic stem cells.

Neuronal development

GPR126 is necessary for Schwann cell myelination. Knockouts of this GPCR in both Danio rerio and Mus musculus result in an arrest at the promyelinating stage. Schwann cells arise from the neural crest that migrate to peripheral nerves to form either myelinating and non myelinating cells. In GPR126 knockouts, these precursor cells develop to the promyelinating stage, where they have wrapped aproximatley 1.5 times. Myelination is arrested at the promyelinating stage and in fish no myelin basic protein can be detected. In fish this can be rescued by adding Forskolin during development, which rescues myelin basic protein expression.

Miscellaneous

Cross Talk

GPCRs downstream signals have been shown to interact with integrin signals, such a FAK. (in GPCR page)

Diffs

GPCRs: cross talk [40]

Adhesion-GPCRs: [41]

future papers

• A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis

• Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma

Assignment 7

VlgR1:

The adhesion GPCR Very Large GPCR receptor 1 (Vlg1R1) is the largest GPCR known, with a size of 6300 amino acids and consisting of 90 exons. There are 8 splice variants of VlgR1, named VlgR1a-1e and Mass1.1-1.3. The N-terminus consists of 5800 amino acids containing 35 Calx-beta domains, one pentraxin domain, and one epilepsy associated repeat. Mutations of VlgR1 have been shown to result in Usher's syndrome. Knockouts of Vlgr1 in mice have been shown to phenocopy Usher's syndrome and lead to audigoenic seizures.

The Sea Urchin genome has a homolog of Vlgr1 in it.

BaI3:

The adhesion GPCR BaI3 is an orphan receptor that has a long N-terminus consisting of one cub domain, five BaI Thrombospondin type 1 repeats, and one hormone binding domain. BaI3 is expressed in neural tissues of the central nervous system. BaI3 has been shown to have a high affinity for C1q proteins. C1q added to hippocampal neurons expressing BaI3 resulted in a decrease in the number of synapses.

CD97:

CD97 is an adhesion GPCR that is normally found on tissue of hematapoetic origin and in smooth muscle. It signals through Gα12/13 and activates RHO. It has been found to be upregulated in Cancers, including prostate, breast, and thyroid. In prostate cancer. it has been shown that CD97 is hetoerodimerizing with another GPCR, LPAR. The interaction is believed to further enhance the RHO signaling between both receptors.

GPR56 expanded:

GPR56 has been shown to be cleaved at the GPS site and then remain associated with the 7TM domain. In a study where the N-terminus was removed up to N342, the start of the GPS, the receptor became constitutively active and an up regulation of Gα12/13 was seen. When receptors are active they are ubiquitinated and GPR56 lacking an N-terminus was highly ubiquitinated.

EMR2:

EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) is an adhesion GPCR that undergoes GPS autoproteolysis before being trafficked to the plasma membrane. Mutations in the GPS have shown that EMR2 does not need to undergo autoproteolysis to be trafficked, but loses function. EMR2 has been shown to be necessary for in vitro cell migration.

Upon cleavage the N-terminus has been shown to associate with the 7TM, but to also dissociate, giving two possible functions. When the N-terminus dissociates it can be found in lipid rafts. Additionally, the cleaved EMR2 protein 7TM has been found to associate with EMR4 N-terminus.

GPR64:

The adhesion GPCR, GPR64, is an orphan receptor characterized by a long N-terminus with that has been suggested to be highly glycosylated. GPR64's N-terminus has been reported to be cleaved at the GPS domain to allow for trafficking to the plasma membrane. After cleavage the N-terminus is believed to remain non-covalently associated with the 7TM. Male mice lacking GPR64 are infertile.

GPR64 expression has been mostly reported in the male reproductive organs, but more recently has been shown to be expressed in the central nervous system.

Reorganization of the Adhesion GPCRs:

There are 33 human adhesion GPCRs that can be broken down in the 8 groups and 2 independent receptors. Group I consists of Lec1,Lec2,Lec3, and ETL. Group II consists of CD97, EMR1, EMR2, EMR3, and EMR4. Group III consists of GPR123, GPR124, and GPR125. Group IV consists of CELSR1, CELSR2, and CELSR3. Group V consists of GPR133 and GPR144. Group VI consists of GPR110, GPR111, GPR113, GPR115, and GPR116. Group VII consists of BAI1, BAI2, and BAI3. Group VIII consists of GPR56, GPR97, GPR112, GPR114, GPR126, and GPR64. There are two other adhesion GPCRs that are not in these groups, VLGR1 and GPR128.

1. The first thing I noticed was the structure of the article didn't seem to be the best. There is a template about cell signaling pathways that begins with the history/discovery, then the mechanism, then the role, then the human diseases, associated with that structure or pathway, and then the research that is currently being performed on the structure and mechanism. Hopefully this will be a good place to begin. It worked very well for my topic.

    I will consider changing the format with headings, but most likely not until the final set of revisions.

2.Also that list of human adhesion proteins seems like it is sort of in the way and doesn't provide much to the overall article. Maybe putting it towards the end of the article would be good, as a source where people can go and check on one of the many adhesion proteins.

     Moved.

3.There were many places that I felt citations should be made. I was originally going to go through sentence by sentence where I felt there should be citations, but I feel like you know where they should be made. The entire section regarding cleavage had only a couple citations that I felt were not necessary. I completely redid that paragraph as will become apparent later.

     I have the mind set that one citation for relevant chunk of information should be fine, but I will add more where there are strong assertions.   I did not write the cleavage section, but thank you for editing it.

4.I also moved some citations from the beginning of paragraphs to the end of them, as the one citation was referring to the entire paragraph and not just the first sentence.

     sure that works just as well.

5. For the first paragraph under signaling, you indicate a technique used for the identification of molecules interacting with the GPCR. However, I feel like citing this technique with a paper that used the technique would be beneficial for people to see how it was done.

      I will see what I can find.

6. I added citations towards the ends of the paragraphs about the two adhesion proteins listed in the third and fourth paragraphs. I also have an idea that would dramatically change the structure that I will talk about a little bit further on.

     Nice and thank you.

7. The cleavage section needed a whole overhaul of the language that was used. I felt it was much to confusing and complex for many reasons. I have tried to make it so that a causal viewer can come upon the page and read it with good understanding. If a more advanced person wants knowledge, I feel that that is when they should go to the citations. Also, there were only three citations in this entire section and they all referred to other organisms where the GAIN domain is found. I thought this sentence to be pretty useless and have taken it out, among many other words that I felt were unnecessary. If you don't like the change, feel free and put it back the way it was. I feel that this is more of the style that Wikipedia is going after, however. I didn't want to go in and change everything about the article, but I wanted to provide this as an example for how it should be done I feel. The page is yours, however, so feel free to make the changes you feel should be made. I am just providing that as an example.

     That section was again not written by me but I will follow your lead and put some more focus on adding clarity to it.

8.The section on the immune system I found to be very hard to read. As someone with some background knowledge regarding biology at this level, I still found it very difficult to read through.

    Again not written by me, but I will work on that one too.  

9. The sentence regarding the BAI1 adhesion protein, I redid as well. I thought that by stating what the protein was thought to be involved in and then stating what it actually is involved in was too similar to the review article this came from. It also, at least for me, adds nothing to my knowledge and current understanding about the protein if it is listed about what the protein was thought to have been involved in.

10.I liked the way the GPCR adhesion protein GPR126 was described in the Neuronal Development section. I liked that it had multiple citations, and the way the information on this page was written was not anywhere similar to the way that it was presented in the articles that cited it. I thought that was very well done.

    Why thank you.

11.I didn't like the way that GPR56 was addressed in the entire article. Little pieces of it are found everywhere. A paragraph is devoted to it in the ligand section. There is a sentence about it in the immune system section, a sentence about it in the bone marrow section, and a sentence about it in the bilateral frontoparietal polymicrogyria section. This brings me to a main point that I had regarding the article as a whole. I feel that a much better structure for this article were to describe each GPCR adhesion protein as if it were its own perhaps mini article, where the ligands, signaling, functional roles, and roles in disease were all put into one section that was all under the heading of the GPR56. Perhaps a better method would be to even put most of this information in the GPR56 page of wikipedia. I also noticed with the GPR12 protein, there was more information on the GPCR adhesion protein in this article than there was on the actual GPR12 article itself. It might be hard to figure out where the information should go, especially if you are trying to fix the main article, regarding ahesion GPCRs. I went searching on Pubmed for general review articles about adhesion GPCRs and found several that seemed to be very good places to begin, as a sort of overview of the GPCR adhesion proteins in general. It seemed like many of the articles that you have cited are primary articles, that could be very dense and hard to get through, while coming to a conclusion that yields the same knowledge that one sentence of a review article could provide. Those primary articles also seem to focus in on one mechanism or structure of one GPCR adhesion protein without addressing what you want to be addressing, which is the overall view of GPCR adhesion proteins.

    I will mull this over for a few days and then maybe make the moves as you suggest.

12. This leads me to another very important point, which is that the way you cited the articles, one on Wikipedia is not simply able to follow the link to a website such as Pubmed. I have included where you can use citations for the Pubmed journal articles Wikipedia template filling tool. I will do a couple for you. When doing this, you need to make sure you press the "Add ref tag" button below. I think it is very important to make them so you are able to follow the link to the article online. I feel that this is very important for someone who is doing some research of their own and have gone to Wikipedia as a starting place. In the past, I have gone to a Wikipedia page to mainly look for articles that were cited at the bottom of the page and not pay heed to the information that was presented at the top. Here are a few more things about the citations, upon which I clicked on and delved into the article a bit. In the second paragraph of signaling, regarding the GPR133 protein, the wording you used and the wording that was used in the research article is very similar, except where you use "via" they use the word "through."

13. For the the citation regarding the Lat-1 protein, I felt that the sentence summed up the article very well without directly copying any of their specific word usage. I thought that this was very well done. I thought that the paragraph was a little wordy as well. I feel like you could simply state that the GPS domain and the 7 transmembrane domain are required for the Lat-1 signaling. In addition, I was not convinced after going into the article that the GPS site was necessary as part of an endogenous ligand. But you have probably read it more clearly than I have. In addition, when you link to the GPS, it gives you the Global Positioning System page, and not the GPS you are talking about.

14. For the citation and the overall entry about the bone marrow GPCR adhesion protein, I felt that taking one sentence from the primary literature on one GPCR adhesion protein and using that as part of a section on the Wikipedia entry of all of the GPCR adhesion proteins may not be the best way to style the article. I also made the sentence more concise.

    I need to add more to it.

Diffs

as of 4/16/2013 Adhesion GPCR

GPR64 diffs

EMR2 diffs

CD97 diffs

BAI3 diffs

VLGR1(GPR98) diffs

Assignment 8

part 1 peer review

These are responses to comments from Biosthmors as I did not find Grace's suggestions.

1. I will see what I can do with the rewording of the intro paragraph: In the lead paragraph, I am deleting the first paragraph because it is repeated in a later section. This should help shorten the lead. Other changes may follow. I feel the lead offers a good "abstract" style for the article and although it may be long is informative for those that would like to skim and get a general idea of what Adhesion GPCRs are.

2. I added adhesion g protein coupled receptor to the beginning.

3. The not so recent work that recently says "recently" is not mine, but that recent work will soon become recently changed. The current work of mine that currently says currently in two places is currently about to be changed concurrently of one another.

4. Super- means very large combined with family meaning all those persons considered as descendants of a common progenitor. Redirecting to protein family should be enough.

5. Not my work, but I will correct it. I think metazoans is fine as people should learn what it means... I will link it as well.

6.I would agree a table may be better, but I think for now it is fine.

7. I left it in for a quick reference at the bottom, but will delete it.

8. yes? The proposed part was removed seemed a little strange.

10. Thank you!

11. Possibly in future revisions

12. I think Adhesion-GPCR is good for now as a tittle, but that is something that I think people should know what GPCR stands for and can easily find out.

Here are the Difs

part two peer review of other articles

All suggestions are made on the peer review area of each article.

-Matt's plant article is very well done and I do like his use of bullet points. I have no comments as of now to add to the plant article section.

-Caitlin's SR protein article: -linked metazoans. -I think the last line of the lead could be put else where.

-Max's small vesicles is pretty good covers a broad range of topics and gives insights into not just signaling and mechanisms of release, but into disease implications as well. No comments or changes as of yet.

-Julia's GST article: -"GSTs can constitute up to 10% of cytosolic protein in some mammalian organs" would it be possible to say what organs?

-Grace's WNT is good.

-Bobby's mTor: -There are some differences with the bold font for titles of sections.

References

Arthur-Farraj, P., Wanek, K., Hantke, J., Davis, C. M., Jayakar, A., Parkinson, D. B., Mirsky, R. and Jessen, K. R. (2011), Mouse schwann cells need both NRG1 and cyclic AMP to myelinate. Glia, 59: 720–733. doi: 10.1002/glia.21144

This concludes Hakkinen2013's user, user talk, and sandbox pages.

Jnims

I am editing Wikipedia as part of this assignment for my first semester of graduate school at SLU. Here is a link to my sandbox.

This user is a member of WikiProject Molecular and Cell Biology.

Assignment 2

[42] [43] [44] [45]

Assignment 3

I have selected Glutathione S-transferase as my main project article.

Assignment 4

[46] [47] [48] [49] [50] [51]

Assignment 6

I realize I haven't added 8 paragraphs of content, but I have moved things around, responded to and complied with suggestions, created new sections, worked on cleaning up the article, etc., in addition to adding three or so new paragraphs. I hope it will suffice, for now. Jnims (talk) 04:55, 19 April 2013 (UTC)

Responses to Ian's suggestions: [52]

Responses to Grace's suggestions: [53]

Article changes: [54] [55] [56] [57] [58] [59] [60] [61] [62]

Welcome

Nice work uploading a picture already! Welcome. Biosthmors (talk) 20:06, 23 January 2013 (UTC)

And if you want to "officially" display the template that says "This user is a member of WikiProject Molecular and Cellular Biology" then you should put it on your user page, User:Jnims. Best! Biosthmors (talk) 20:07, 23 January 2013 (UTC)

Article topic for Biol 512

Taking a quick look at the links you posted on my talk page, it looks like you've found some good resources and I agree with your assessment about editing the Glutathione_transferase article over the other two. Biolprof (talk) 02:14, 4 February 2013 (UTC)

Assignment 3

The information looks good from a good search and search through your articles in the posted references. I would like to have the references added to your current ref section and them inserted next to the relevant sentences. Hakkinen2013 (talk) 04:28, 19 February 2013 (UTC)

Assignment 3

I agree with Ian. I have learned that keeping track of the citations right off the bat has always helped organize things much better. It saves much wasted time trying to go back and figure out where each source came from and then just giving up trying to figure it out. This may seem like common sense, but I still have yet to get this idea fully incorporated into my own research as of yet. Flemingrjf (talk) 05:36, 19 February 2013 (UTC)

Assignment 3 feedback

Thanks for the suggestions, Ian and Bobby. Actually, all the information I got came from that one citation, but I plan to expand it in the future, of course.

Jnims (talk) 19:35, 19 February 2013 (UTC)

Assignment 3

Your formatting looks to be in good shape. Keep up the good work. Gpruett2 (talk) 04:24, 21 February 2013 (UTC)

Reply

Hello, Biosthmors. You have new messages at Biosthmors's talk page.
You can remove this notice at any time by removing the {{Talkback}} or {{Tb}} template.

Biosthmors (talk) 05:17, 19 March 2013 (UTC)

Assignment 5

Ian's Review of Glutathione S-transferase

Julia's responses below each of Ian's points, below. Jnims (talk) 21:09, 17 April 2013 (UTC)

Your work:

(structure)

• Add a Citation end note in the first paragraph. I think it would be reference 7 again there. From the 2011 Glutathione transferases: a structural perspective paper
  • Right you are. Done.

• the UniProtKB/Swiss-Prot database can be linked as uniprot
  • Done.

• I am a little bit confused by the maxed all species column. Does it mean that that is highest number that has been found out of all species? (the chart is good otherwise)
  • That's a great question! I have absolutely no idea, and am wholly unfamiliar with protein databases. I will try to contact the user who made the chart originally, in the hope of gaining insight.

• Good information. The second paragraph may be a good place to add more for your next revision, possibly expanding and adding more details about the information that you already have.
  • Thanks; I will focus on this area for Assignment 6.

(role in cell signaling)

• Paragraph 1 is a good intro and set up for what comes.
  • Thank you kindly.

• paragraph 2 needs a citation where you say "in fact"
  • Done.

• I think each example you give about the different classes of GST provides good details and that is the best way to do it.
  • Excellent, thanks.

(implications in cancer)

• Nice picture for the possible ways that GST can play a role in cancer.
  • Thanks; I thought so, too.

The Previous Material:

• I find the introduction to be a bit wordy and confusing. It took me several reads to get a gist of what is trying to be said. A possible place for revisions in the future.
  • I agree, and will work on improving it for Assignment 6.

• The Gst and Biotransformation heading could be just biotransformation.
  • Good point. Done.

• There is a logical flow to the article and it definitely is a good start for this addition.
  • Thanks!

— Preceding unsigned comment added by Hakkinen2013 (talk • contribs) 04:39, 26 March 2013 (UTC)

Help us improve the Wikipedia Education Program

Hi Jnims! As a student editor on Wikipedia, you have a lot of valuable experience about what it's like to edit as a part of a classroom assignment. In order to help other students like you enjoy editing while contributing positively to Wikipedia, it's extremely helpful to hear from real student editors about their challenges, successes, and support needs. Please take a few minutes to answer these questions by clicking below. (Note that the responses are posted to a public wiki page.) Thanks!

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Assignment 5 feedback from Gpruett2

Grace was kind enough to provide suggestions for me, as well, so I've included them below, followed by my responses. Jnims (talk) 00:49, 18 April 2013 (UTC)

• The first big thing that I note is that several paragraphs that you did not edit (the ones under “GSTs and biotransformation” and “GST-tags and the GST pull-down assay”) and one that you did (first paragraph under “Structure”) have no citations. These paragraphs list specific information; thus, it is vital that they be cited.
  • I will try to find citations for the content I did not add. I've added a citation to the Structure section.

• Another issue that I noted is that while one section is titled “Structure”, I feel like it is mostly discussing how GSTs are divided into different classifications. I would suggest either separating the information about structure and classification into two different sections or re-labeling this section.
  • Good point. From your suggestion, I have decided to separate the information into two sections: Structure and Classification.

• Furthermore, you should consider rewording the first paragraph under “Structure”. Specifically, make sure that it is obvious that GST proteins are classified as belong to one of the three different families (cytosolic, mitochondrial, or MAPEG). I say this because when I first read this paragraph, I wasn’t sure of how the sentences starting with “Cytosolic GSTs”, “Mitochondrial GSTs”, and “The MAPEG superfamily” related to one another.
  • I have attempted to clarify the wording.

• Also, while the writing is very sound and the information in the different sections are relevant to one another, I feel like a lot of the paragraphs under your sections seem rather disjointed. They do not transition well between each other. For example, under “Role in Cell Signaling”, you go from talking about the effects of GST on MAPK signaling to talking about the location of GSTπ. For me as a reader, I find this distracting and confusing. To remedy this, perhaps start the GSTπ paragraph with an introduction sentence that mentions it is related to cell signaling. Overall, with all of the paragraphs that are together under a section, try to make them flow together.
  • I will work on knitting the sections together more effectively, although I believe the GSTP paragraph is fine as it stands, as the second sentence relates it to cell signaling. I tried in the past to make it more obvious, but could not find a good way to include all the necessary information about the meaning of the name "GSTP1-1" without putting off the cell signaling tie-in until the second sentence.

• Generally, I also suggest that you might want to reconsider the overall structure and organization of your article. The WikiProject Molecular and Cellular Biology Style Guide has a good suggestion for the different sections that should be included in a protein article.
  • I am currently working on a Function section, and would also like to add a section about the history/discovery of the protein superfamilies, if possible. Additionally, I would like to include a Clinical significance section, as you suggest below. While a Gene section is in theory appealing, the huge array of isozymes and superfamilies and classes of GSTs may make such a section of dubious value.

• Specifically, you should probably move the “Role in cell signaling” and “Implications in cancer development” sections out from under “Structure”. They do not seem to be specifically related to structure and/or they do not really discuss structure; thus, they should not be listed under structure.
  • I hadn't even noticed that. Thanks! It is fixed.

• I also moved one of your citations. I place citation [8] next to citation [9] at the end of the sentence because that is where I believe Wikipedia likes to have citations.
  • Much obliged.

• I also have some suggestions for sections that you might want to include in your article. One such section would be “Clinical significance” or “Implications in disease”. This would be a good section to not only discuss GST involvement in cancer, but also other conditions. For instance, citation [4] lists several other conditions (such as Parkinson’s, Alzheimer’s, and cardiovascular disease) that are associated with malfunctioning GST. Another useful section would be a “History” or “Discovery” section. While Wikipedia asks that you not specifically list who conducted each study in GST, it does say that you can mention those who made key discoveries. Also, this section could discuss what experiment was used to first discover GST.
  • I would like to create both of these sections (see above). Thank you for the suggestions!

This is my test sentence. Here is an article about signal transduction.

Useful links

Course page

Advice for students

Orientation for students

Cheatsheet

Wiki markup

Editing Wikipedia for scientists

WikiProject: Molecular and Cellular Biology

WikiProject: Cell Signaling

Reliable sources (natural sciences)

Avoiding plagiarism

Gene & protein article style guide

Proposed WikiProject: Cell Signaling article structure

Reference template tool

Instructions for reference template tool

Citation tools

National varieties of English

Manual of Style

Template messages/cleanup

Project article: Glutathione S-transferase

Assignment 3

Glutathione S-transferase structure

Protein sequence and structure are important classification methods for GSTs: while classes from the cytosolic superfamily of GSTs possess more than 40% sequence homology, those from other classes may have less than 25%. Cytosolic GSTs are divided into 13 classes based upon their structure: alpha, beta, delta, epsilon, zeta, theta, mu, nu, pi, sigma, tau, phi, and omega. Mitochondrial GSTs are in class kappa. The MAPEG superfamily of microsomal GSTs consists of subgroups designated I-IV, between which amino acid sequences share less than 20% identity.

The glutathione binding site, or "G-site," is located in the thioredoxin-like domain of both cytosolic and mitochondrial GSTs. The region containing the greatest amount of variability between the assorted classes is that of helix α2, where one of three different amino acid residues interacts with the glycine residue of glutathione. Two subgroups of cytosolic GSTs have been characterized based upon their interaction with glutathione: the Y-GST group, which uses a tyrosine residue to activate glutathione, and the S/C-GST, which instead use serine or cysteine residues.

Bibliography of relevant research

Glutathione transferases: a structural perspective

Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death

Assignment 4

Ideas (TEMPORARY):

• Infobox detailing orthologous structure in human genome as per infobox guidelines for gene & protein articles, specifically GNF protein box
• Gene information

Structure

Protein sequence and structure are important classification methods for GSTs: while classes from the cytosolic superfamily of GSTs possess more than 40% sequence homology, those from other classes may have less than 25%. Cytosolic GSTs are divided into 13 classes based upon their structure: alpha, beta, delta, epsilon, zeta, theta, mu, nu, pi, sigma, tau, phi, and omega. Mitochondrial GSTs are in class kappa. The MAPEG superfamily of microsomal GSTs consists of subgroups designated I-IV, between which amino acid sequences share less than 20% identity.

The glutathione binding site, or "G-site," is located in the thioredoxin-like domain of both cytosolic and mitochondrial GSTs. The region containing the greatest amount of variability between the assorted classes is that of helix α2, where one of three different amino acid residues interacts with the glycine residue of glutathione. Two subgroups of cytosolic GSTs have been characterized based upon their interaction with glutathione: the Y-GST group, which uses a tyrosine residue to activate glutathione, and the S/C-GST, which instead use serine or cysteine residues.

The porcine pi-class enzyme pGTSP1-1 was the first GST to have its structure determined, and it is representative of other members of the cytosolic GST superfamily, which contain a thioredoxin-like N-terminus domain as well as a C-terminus domain consisting of alpha helices.

Role in cell signaling

A simplified overview of MAPK pathways in mammals, organised into three main signaling modules (ERK1/2, JNK/p38 and ERK5).

Although best known for their ability to conjugate GSH and thereby detoxify cellular environments, GSTs are also capable of binding nonsubstrate ligands, with important cell signaling implications. Several GST isozymes from various classes have been shown to inhibit the function of a kinase involved in the MAPK pathway that regulates cell proliferation and death, preventing the kinase from carrying out its role in facilitating the signaling cascade.

The cytosolic π-class GST composed of subunit 1 homodimers (GSTP1-1), a well-characterized isozyme of the mammalian GST family, is expressed primarily in heart, lung, and brain tissues; in fact, it is the most common GST expressed outside the liver. Based on its overexpression in a majority of human tumor cell lines and prevalence in chemotherapeutic-resistant tumors, GSTP1-1 is thought to play a role in the development of cancer and its potential resistance to drug treatment. Further evidence for this comes from the knowledge that GSTπ can selectively inhibit C-jun phosphorylation by JNK, preventing apoptosis. During times of low cellular stress, a complex forms through direct protein-protein interactions between GSTπ and the C-terminus of JNK, effectively preventing the action of JNK and thus its induction of the JNK pathway. Cellular oxidative stress causes the dissociation of the complex, oligomerization of GSTπ, and induction of the JNK pathway, resulting in apoptosis. The connection between GSTπ inhibition of the pro-apoptotic JNK pathway and the isozyme's overexpression in drug-resistant tumor cells may itself account for the tumor cells' ability to escape apoptosis mediated by drugs that are not substrates of GSTπ.

Like GSTπ, GSTμ 1 (GSTM1) is involved in regulating apoptotic pathways through direct protein-protein interactions, although it acts on ASK1, which is upstream of JNK. The mechanism and result are similar to that of GSTπ and JNK, in that GSTM1 sequesters ASK1 through complex formation and prevents its induction of the pro-apoptotic p38 and JNK portions of the MAPK signaling cascade. Like GSTπ, GSTM1 interacts with its partner in the absence of oxidative stress, although ASK1 is also involved in heat shock response, which is likewise prevented during ASK1 sequestration. The fact that high levels of GST are associated with resistance to apoptosis induced by a range of substances, including chemotherapeutic agents, supports its putative role in MAPK signaling prevention.

Implications in cancer development

There is a growing body of evidence supporting the role of GST, particularly GSTP, in cancer development and chemotherapeutic resistance. The link between GSTP and cancer is most obvious in the overexpression of GSTP in many cancers, but it is also supported by the fact that the transformed phenotype of tumor cells is associated with aberrantly regulated kinase signaling pathways and cellular addiction to overexpressed proteins. That most anti-cancer drugs are poor substrates for GSTP indicates that the role of elevated GSTP in many tumor cell lines is not to detoxify the compounds, but must have another purpose; this theory is also given credence by the common finding of GSTP overexpression in tumor cell lines that are not drug resistant.

Assignment 6 (NOT FINAL)

Ideas (TEMPORARY):

• New section: Gene
  • Information about polymorphisms, etc. May not work because of huge variety of superfamilies, classes, isozymes, etc.
• New section: Clinical significance
  • See Gpruett2's suggestions
• New section: History/Discovery
  • How to do this without using primary sources?
• Follow these guidelines for new sections.

All-new content below! Other changes to GST article documented on user page.

Function

The function of GSTs is dependent upon a steady supply of GSH from the synthetic enzymes gamma-glutamylcysteine synthetase and glutathione synthetase, as well as the action of specific transporters to remove conjugates of GSH from the cell. The primary role of GSTs is to detoxify xenobiotics by catalyzing the nucleophilic attack by GSH on electrophilic carbon, sulfur, or nitrogen atoms of said nonpolar xenobiotic substrates, thereby preventing their interaction with crucial cellular proteins and nucleic acids. Specifically, the function of GSTs in this role is twofold: (1) to bind both the substrate at the enzyme's hydrophobic H-site and GSH at the adjacent, hydrophilic G-site, which together form the active site of the enzyme; (2) and subsequently to activate the thiol group of GSH, enabling the aforementioned nucleophilic attack upon the substrate. The compounds targeted in this manner by GSTs encompass a diverse range of environmental or otherwise exogenous toxins, including chemotherapeutic agents and other drugs, pesticides, herbicides, carcinogens, and variably-derived epoxides; indeed, GSTs are responsible for the conjugation of β₁-8,9-epoxide, a reactive intermediate formed from aflatoxin B₁, which is a crucial means of protection against the toxin in rodents. The aforementioned detoxification reactions comprise the first four steps of mercapturic acid synthesis, with the conjugation to GSH serving to make the substrates more soluble and allowing them to be removed from the cell by transporters such as multidrug resistance-associated protein 1 (MRP1). After export, the conjugation products are converted into mercapturic acids and excreted via the urine or bile.

Gallery

• 
  I made this myself.

Notes

This concludes Jnims's user, user talk, and sandbox pages.

Flemingrjf

I'm Bobby Fleming. A senior at Saint Louis University. I am using wikipedia for a biology class in Signal Transductions.

I'm editing Wikipedia as part of this assignment and here's a link to my sandbox.

The Wikipedia article I have selected to edit is mTOR as well as the two related articles mTORC1 and mTORC2.

Assignment 4

For assignment 4, I mostly rebuilt the mTORC1 page by keeping the main content there, but adding much more detail to it as well as vastly updating the citations in terms of year published as well as their content. I am pretty proud of the efforts there so far and feel that the page is almost complete. I also added a history of mTOR to the mTOR page as well. I have added as much as I have could find about mTORC2, but feel with more digging into the literature a review article describing in greater mTORC2 will arise. For the next major assignment in terms of editing, I plan on adding pictures to the mTORC1 article, which includes pathways as well as structure of mTORC1. In addition, I also plan on adding an overall picture of the mTOR pathway, which includes both mTOR complexes as the picture describing the pathway right now seems rather confusing to the casual researcher. Below I have included the more significant diffs as lots of them were very minor (like taking out a word here or there) and can be looked upon by going to the page histories of either mTOR, mTORC1 or mTORC2.

[63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73]

Assignment 6

For assignment 6, I added the clinical significance to the mTORC1 page. I am pretty proud with the efforts there. With the clinical aspects, I tried to make them as understandable to the very casual reader as I could. I feel that, hopefully, a reader will be able to pass upon mTORC1, and hopefully become a healthier and overall better person as a result of reading the article. In addition, I have also addressed all of Grace's comments on the talk page for mTORC1. In terms of my revision of the article, I wanted to focus on how mTORC1 was able to influence aging throughout the entire body while referencing its effects on cancer, diabetes, neurodegenerative disease, and cardiovascular disease. In the future, I hope to specifically address these aspects of aging in terms of mTORC1's influence on them. The first priority in future revisions to the mTORC1 article are to create pictures of the different signalling going on as well as get rid of the disambiguity of the links on the page. A rough draft of the picture in regards to signalling has been created on a powerpoint slide, but I am not ready to upload it yet. I will also try to get my article linked with as many related articles as possible, in order to create public interest in this page, because mTORC1 and its signalling seems so consequential for overall human health. One review article I read said that even though on the surface, aging and decline seems to be very complicated, it can all be traced back to mTOR. This may be oversimplifying it, but the point does get across. Below, I have included the more significant diffs to the page. I hope the links work, even though a picture of a lock appears next to them.

[74] [75] [76] [77] [78] [79] [80] [81]

This user is a member of WikiProject Molecular and Cellular Biology.

References

Hello there! It looks like you created your user page in your sandbox. When you create your user page, your name will no longer appear red. Welcome to Wikipedia! =) Biosthmors (talk) 19:16, 22 January 2013 (UTC)

assignment topic

I think that mTOR looks like a great topic for both your lecture and for the WikiProject. The mTOR pathway does split with the two different complexes, so you may end up working on all three articles, but now that they have been split apart, some editing and rewriting seems needed. Biolprof (talk) 21:05, 7 February 2013 (UTC)

Assignment 3 copy editing

I have highlighted some sentences and phrases that I would like for you to clarify or edit, but did not feel comfortable manipulating myself, due to my lack of knowledge on the topic. Your own writing is in quotation marks, followed by my observations. (They are not necessarily in order of how you wrote them, sorry!)

• "It is important to note, that only the mTORc1 complex has been shown to be inhibited by rapamycin."

This sentence seems out of place in the rest of the paragraph. Could you either elaborate on it, integrate it better, or place it elsewhere? (It's in the second paragraph, sixth sentence.)

• "The NR (negative regulatory) domain is the putative negative regulatory region of the mTOR complexes."

This is redundant. Could you rephrase the latter portion somehow? I realize you can't rename the domain itself, of course.

• "The mammalian target of rapamycin (mTOR) is considered a 'master switch' of cellular processes"

Where did you get the phrase "master switch?" Please cite it appropriately or remove the single quotation marks, which are misleading.

• "the initial mTOR protein"

What do you mean by this? (It's in the first paragraph and fourth or fifth sentence, I believe.)

• "mTORc1 and 2 share the same core protein complex of 2549 amino acids, which contains seven conserved domains, written from the N- to the C- terminus as HEAT, FAT, FRB, kinase, NR, and FATC domains."

Could you reword the latter portion of this sentence to make it clearer?

Jnims (talk) 23:16, 18 February 2013 (UTC)

Ian's Fact Checking

Looks good to me. — Preceding unsigned comment added by Hakkinen2013 (talk • contribs) 04:19, 19 February 2013 (UTC)

Assignment 3 Wikipedia Editing

You have done a good job citing your sources; however, if you are using the same source to cite consecutive sequences, you could probably consolidate the in-text citations instead of citing every sentence in some cases in your edit. Gpruett2 (talk) 04:16, 21 February 2013 (UTC)

Response to These Peer Reviews

• Jnims - none of those sentences have made it to the official wikipedia pages.
• Hakkinen2013 - thanks!
• Gpruett2 - I have kept that in mind during my work on the articles

Help us improve the Wikipedia Education Program

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mTORC1 article

I saw your message on my talk page and had a quick look over the mTORC1 article. It looks like the article is in very good shape, and is well structured and referenced and seems accurate. Personally I think the biggest improvement you could now make is accessibility; when writing anything you need to think about the target audience. Currently the article is at the level of complexity of a specialised review, someone outside of the field will have difficulty getting into the topic. This certainly doesn't mean detail should be removed, just introduced more clearly and with less specialist terms.

For a comparison have a read of Einstein's theory of relativity article. This is obviously a much bigger topic than mTORC1, but look at how it is introduced. A non-physicist would have a good idea about what it is talking about.

I hope this helps! - Zephyris _Talk 14:12, 23 April 2013 (UTC)

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mTOR

Raptor
Identifiers
Symbol	RPTOR
NCBI gene	57521
HGNC	30287
OMIM	607130
RefSeq	NM_020761
UniProt	Q8N122
Other data
Locus	Chr. 17 q25.3
Search for Structures Swiss-model Domains InterPro

MLST8
Identifiers
Symbol	MLST8
NCBI gene	64223
HGNC	24825
OMIM	612190
RefSeq	NM_022372
UniProt	Q9BVC4
Other data
Locus	Chr. 16 p13.3
Search for Structures Swiss-model Domains InterPro

PRAS
Identifiers
Symbol	AKT1S1
NCBI gene	84335
HGNC	28426
OMIM	610221
RefSeq	NM_032375
UniProt	Q96B36
Other data
Locus	Chr. 19 q13.33
Search for Structures Swiss-model Domains InterPro

DEPTOR
Identifiers
Symbol	DEPTOR
Alt. symbols	DEPDC6
NCBI gene	64798
HGNC	22953
OMIM	612974
RefSeq	NM_022783
UniProt	Q8TB45
Other data
Locus	Chr. 8 q24.12
Search for Structures Swiss-model Domains InterPro

History/Discovery

mTOR is considered to be the mammalian target of rapamycin. Rapamycin was discovered in a soil sample from Easter Island in the 1970s. Researchers studied this sample and found that the bacterium Streptomyces hygroscopicus made an antifungal, which they named rapamycin after the island's name Rapa Nui, which it was called by the locals meaning "navel of the world." Studies on rapamycin revealed that it was a powerful antifungal agent that could arrest fungal activity at the G1 phase. It was then tested in rats as a potential antifungal drug in humans, and was found to also greatly suppress their immune system by blocking the G1 to S phase transition in T-lymphocytes. This has led to its clinical use as an immunosupressant following organ transplantation.

In 1991, a genetic screen was performed on Saccharomyces cerevisiae to elucidate what rapamycin was specifically targeting to initiate this response. It was found that knockout of three genes allowed for the fungus' resistance to rapamycin. Two of the genes were called targets of rapamycin, or TOR, while the third gene was already characterized to be Fpr1, which is now known to be a binding protein in the TOR complexes. In 1994, the mammalian target of rapamycin (mTOR) was identified at the rapamycin target in mammals.

mTOR Structure

The mammalian target of rapamycin (mTOR) is considered a 'master switch' of cellular processes, regulating transcription of proteins required for cell growth and proliferation by sensing energy and nutrient levels. As a result, it plays an important role in various human diseases, including cancer and diabetes. mTOR consists of two structures, mTOR complex 1 (mTORc1) and mTOR complex 2 (mTORc2). mTORc1, named for its putative sensitivity to rapamycin, is the better-studied component of the mTOR protein and is thought to play the principal role in the initial mTOR protein; it is believed to regulate cell growth, proliferation, and survival by integrating hormones, growth factors, nutrients, stressors, and energy signals. mTORc2 is thought to regulate cytoskeleton and cell survival in response to insulin, although the upstream signaling pathways have yet to be fully elucidated.

mTORc1 and 2 share the same core protein complex of 2549 amino acids, which contains seven conserved domains, written from the N- to the C- terminus as HEAT, FAT, FRB, kinase, NR, and FATC domains. The largest domain is called the HEAT repeat domain, named for the Huntingtin, Ef2, A subunit of PP2A, TOR1 amino acid repeats that it contains. The HEAT domain is implicated in protein-protein interactions. The FAT domain I need to research more about. The FRB domain is specifically targeted by rapamycin for inhibition for the mTOR complexes. It is important to note, that only the mTORc1 complex has been shown to be inhibited by rapamycin. The kinase domain is the catalytic domain responsible for phosphorylating serine and threonine residues on target proteins. Attached to the kinase domain is the mLST8 domain, the mammalian ortholog of the LST8 protein first discovered in yeast. mTORc2 has been shown to require this domain for function, and it has been suggested that it is also required in mTORc1. The NR (negative regulatory) domain is the putative negative regulatory region of the mTOR complexes. The FATC domain, or FAT domain on the C-terminus, has been shown to be necessary for the kinase function of mTOR, as a single amino acid deletion from this sequence prevents such activity.

There are two complexes that contain the mTOR core protein: mTOR complex 1 and mTOR complex 2 named mTORC1 and mTORC2 respectively.

The mTOR core protein is 2549 amino acids long and contains a HEAT repeats domain, FAT domain, FRB domain, kinase domain, NR domain, and FATC domain. The HEAT domain spans the first half of the core protein and consists of many tandem HEAT repeats which stands for the amino acid sequences for the domains of for Huntingtin, EF3, A subunit of PP2A, and TOR1. These HEAT repeats are considered to be for protein-protein interactions with either Raptor or Rictor for mTORC1 or mTORC2, respectively. FAT lies downstream of the HEAT region and will interact with the FAT C terminal domain and this interaction is thought to modulate the kinase activity of mTOR. This FATC domain is so conserved that changing one amino acid in this sequence has been shown to disrupt mTOR activity. The FRB (FKB12-rapamycin binding) domain is the stretch of amino acids that rapamycin binds to in order to inhibit mTOR activity. The NR domain is located just before the FATC domain on the C terminus and is a putative negative regulatory region, where substrates can bind to inhibit mTOR activity.

The mTORC1 and mTORC2 complexes differ due to the associated proteins that make up their complexes.

mTORc1 and mTORc2 both have specific regulatory proteins, known as Raptor and Rictor, respectively. I will go on to talk about Raptor and Rictor next time.

mTORC1

Upstream of mTORC1

The role of mTOR is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for protein translation to begin.

All of these variables for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 complex. TSC2 is a GTP-ase activating protein (GAP). Its GAP activity interacts with Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways. Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer. This control is usually performed through phosphorylation of the complex, which can cause the dimer to dissociate losing its GAP activity, or the phosphorylation can cause the heterodimer to have more active GAP activity, depending on the kinase phosphorylating the dimer.

Growth Factors

Growth factors like insulin can activate mTORC1 through the receptor tyrosine kinase (RTK) pathway. Ultimately Akt phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3 to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling .

Akt will also phosphorylate PRAS40, causing it to fall off of Raptor on mTORC1. PRAS40 prevents Raptor from recruiting mTORC1's substrates 4E-BP1 and S6K-1. Thus when PRAS40 falls off of Raptor, the two substrates are recruited to mTORC1 and thereby activated in this way.

Because insulin is a factor that is secreted by pancreatic beta cells upon glucose elevation in the blood, this signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop, S6K-1 is able to phosphorylate the insulin receptor, and inhibit its sensitivity to insulin. This has great significance in diabetes mellitus, which is due to insulin resistance.

Mitogens

Mitogens like insulin like growth factor 1 (IGF1) can activate the Ras-ERK pathway, which can control the TSC1/TSC2 complex as well as directly have the same downstream role that mTORC1 has. In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 gets binds with its SH2 domains. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf (MAPKKK), which activates Mek (MAPKK), which activates Erk (MAPK). Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2. These phosphorylations will cause the heterodimer to fall apart, and not be able to deactivate Rheb. This, thus keeps mTORC1 active.

RSK has also been shown to phosphorylate Raptor, which helps it overcome the inhibitory effects of PRAS40.

Cytokines

Cytokines like tumor necrosis factor alpha (TFNalpha), can induce mTOR activity through IKK beta. IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP bound state.

Energy Status

In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like AMP, and the ratio of AMP to ATP molecules gets too high, AMPK will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.

AMPK can phosphorylate TSC2 on serine residue 1387, which will now activate the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1, and no protein synthesis occurs through this pathway.

AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor now recruits 14-3-3, to bind to it, preventing Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.

LBK1 is a known tumor suppressor that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.

Hypoxic Stress

When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under hypoxic conditions, hypoxia inducible factor one alpha (HIF-1 alpha) will stabilize and activate transcription of REDD1. After translation, this REDD1 protein will bind to TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP, and mTORC1 inactive.

Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress, AMPK will also become active and thus inhibit mTORC1 through its processes.

Wnt Pathway

The Wnt pathway is responsible for cellular growth and proliferation during organismal development. Thus it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3 beta). When the Wnt pathway is not active, GSK3 beta is able to phosphorylate TSC2 on two serine residues of 1341 and 1337, in conjunction with AMPK phosphorylating serine residue 1345. It has been studied that the AMPK is required to first phosphorylate residue 1345 before GSK3 beta can phosphorylate its target serine residues. This phosphorylation of TSC2 would inactivate this complex, if GSK3 beta were active. Since the Wnt pathway inhibits GSK3 signaling, when the Wnt pathway is active, so also is the mTORC1 pathway. Now, mTORC1 can activate protein synthesis for the developing organism.

Amino Acids

Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Consequentially, mTORC1 signaling is sensitive to amino acid levels in the cell. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPases heterodimers to switch to its active conformation. Active Rag heterodimers interact with RAPTOR, localizing mTORC1 to the surface of late endosomes and lysosome where the Rag GTPases are located. This allows mTORC1 to physically interact with RHEB, which is activated by growth factors such as insulin. The interaction between the Rags and mTORC1 brings mTORC1 to the surface of endosomes and lysosomes where Rheb is located. This is where Rheb-GTP activates mTORC1.

Downstream of mTORC1

mTOC1 activates transcription and translation through its interactions with 4E-BP1 and S6K.

4E-BP1

Activated mTORC1 will phosphorylate transcription inhibitor 4E-BP1, releasing it from eukaryotic translation initiation factor 4E (eIF4E). eIF4E is now free to join the eukaryotic translation initiation factor 4G (eIF4G) and the eukaryotic translation initiation factor 4A (eIF4A). This complex then binds to the 5' cap of mRNA and will recruit the helicase eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (eIF4B). The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA, that prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 40S small ribosomal subunit that is now capable of scanning for the AUG codon start site, because the hairpin loop has been eradicated by the eIF4A helicase.

S6K

mTORC1 will also activate S6K, which is responsible for the recruitment of eIF4B to the initiation complex by phosphorylating its serine residue 422.

S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquidin ligase Beta-TrCP. PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.

Active S6K can bind to the SKAR scaffold protein that can get recruited to exon junction complexes. Exon junction complexes span the mRNA region where two exons come together after an intron has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.

Hypophosphorylated S6K is located on the eIR3 scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.

mTORC1 Role in Human Diseases and Aging

mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in S. cerevisiae, doubling its lifespan. As a result, mTORC1 signaling was focused on and techniques used to inhibit its activity in C. elegans, fruitflies, and mice significantly increased their lifespans relative to the control organisms for the respective species.

Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed. Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the lysosome.

Dietary restriction has been shown to significantly increase lifespan in the human model of Rhesus monkeys as well as protect against their age related decline. More specifically, Rhesus monkeys on a calorie restricted diet had significantly less chance of developing cardiovascular disease, diabetes, cancer, and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.

Stem Cells

Conservation of stem cells in the body has been shown to help prevent against premature aging. mTORC1 activity plays a critical role in the growth and proliferation of stem cells. Knocking out mTORC1 results in embryonic lethality due to lack of trophoblast development. Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.

mTORC1 plays a role in the differentiation and proliferation of hematopoietic stem cells. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line. Rapamycin is used clinically as an immunosupressant and prevents the proliferation of T cells and B cells. Paradoxically, even though rapamycin is a federally approved immunosuppressant, its inhibition of mTORC1 results in better quantity and quality of functional memory T cells. mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become memory precursor cells during the expansion phase of T cell development . This inhibition also allows for an increase in quality of these memory T cells that become mature T cells during the contraction phase of their development. mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of B cells in old mice, enhancing their immune systems. This paradox of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with T-regulatory cells. The mechanisms mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated.

Autophagy

Autophagy is the major degradation pathway in eukaryotic cells and is essential for the removal of damaged organelles via macroautophagy or proteins and smaller cellular debris via microautophagy from the cytoplasm. Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures. Autophagy can thus remove aggregates of proteins and damaged organelles, that can lead to cellular dysfunction.

Upon activation, mTORC1 will phosphorylate Atg 13, preventing it from entering the ULK1 kinase complex, which consists of Atg1-Atg17-Atg101. This prevents the structure from being recruited to the preautophagosomal structure at the plasma membrane, inhibiting autophagy..

mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level. Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.

Reactive Oxygen Species

Reactive oxygen species can damage the DNA and proteins in cells. A majority of them arise in the mitochondria.

Deletion of the TOR1 gene in yeast increases mitochondrial respiration by enhancing the translation of mitochondrial DNA that encodes for the complexes involved in the electron transport chain. When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial cortex may accumulate and begin to produce reactive oxygen species. It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis in the cytosol for ATP production rather than through oxidative phoshphorylation in the inner membrane of the mitochondria.

Inhibition of mTORC1 has also been shown to increase transcription of the NRF2 gene, which is a transcription factor that is able to regulate the expression of electrophilic response elements as well as antioxidants in response to increased levels of reactive oxygen species.

mTORC1 Inhibition

Rapamycin was the first known inhibitor of mTORC1, considering that mTORC1 was discovered as being the target of rapamycin. Rapamycin will bind to cytosolic FKBP12 and act as a scaffold molecule, allowing this protein to dock on the FBP regulatory region on mTORC1. The binding of the FKBP12-rapamycin complex to the FBP regulatory region inhibits mTORC1 through processes not yet known.

Rapamycin itself is not very water soluble and is not very stable, so scientists developed rapamycin analogs, called rapalogs, to overcome these two problems with rapamycin. These drugs are considered the first generation inhibitors of mTOR.

Siroliumus, which is the drug name for rapamycin, was approved by the FDA in 1999 to prevent against host rejection in patients undergoing kidney transplantation. In 2003, it was approved as a stent covering for people who want to widen their arteries to prevent against heart attacks and stuff. In 2007, they began being approved for treatments against cancers such as renal cell carcinoma. In 2008 they were approved for mantle cell lymphoma. mTORC1 inhibitors have recently been approved for treatment of pancreatic cancer. In 2010 they were approved for treatment of tuberous sclerosis.

The second generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells. One problem with the first generation inhibitors of mTORC1 is that there is a negative feedback loop from phosphorylated S6K, that can inhibit the insulin RTK via phosphorylation. When this negative feedback loop is no longer there, the upstream regulators of mTORC1 become more active than they would otherwise would have been under normal mTORC1 activity. Another problem is that since mTORC2 is resistant to rapamycin, and it too acts upstream of mTORC1 by activating Akt. Thus signaling upstream of mTORC1 still remains very active upon its inhibition via rapamycin and the rapalogs.

Second generation inhibitors are able to bind to the ATP binding site on the kinase domain of the mTOR core protein itself and abolish activity of both mTOR complexes. In addition, since the mTOR and the PI3K proteins are both in the same PIKK family of kinases, some second generation inhibitors have dual inhibition towards the mTOR complexes as well as PI3K, which acts upstream of mTORC1. As of 2011, these second generation inhibitors were in phase II of testing.

There have been several dietary compounds that have been suggested to inhibit mTOR signaling including EGCG, resveratrol, curcumin, caffeine, and alcohol.

There are currently more than 1,300 clinical trials underway for the mTOR complex inhibitors.

References

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