Regulation
editThe Receptor Tyrosine Kinase (RTK) pathway is carefully regulated by a variety of positive and negative feedback loops. Because RTKs coordinate a wide variety of cellular functions such as cell proliferation and differentiation, they must be regulated to prevent severe abnormalities in cellular functioning such as cancer and fibrosis. (Fawaz et al).[1]
Protein Tyrosine Phosphatases
editProtein Tyrosine Phosphatase (PTPs) are a group of enzymes that possess a catalytic domain with phosphotyrosine-specific phosphohydrolase activity (Ostman et al). PTPs are capable of modifying the activity of receptor Tyrosine kinases in both a positive and negative manner.[2] PTPs can dephosphorylate the activated phosphorylated tyrosine residues on the RTKs (Kovalenko et al, 2000) which virtually leads to termination of the signal. Studies involving PTP1B, a widely known PTP involved in the regulation of the cell cycle and cytokine receptor signaling, has shown to dephosphorylate the epidermal growth factor receptor (Flint et al 1997) and the insulin receptor (Kenner, et al 1996). Some PTPs, on the other hand, are cell surface receptors that play a positive role in cell signaling proliferation. Cd45, a cell surface glycoprotein, plays a critical role in antigen-stimulated dephosphorylation of specific phosphotyrosines that inhibit the Src pathway.[3]
Herstatin
editHerstatin, an autoinhibitor of the ErbB family[4] , which binds to RTKs and blocks receptor dimerization and tyrosine phosphorylation.[5] CHO cells transfected with herstatin resulted in reduced receptor oligomerization, clonal growth and receptor tyrosine phosphorylation in response to EGF.[6]
Receptor Endocytosis
editActivated RTKs can undergo endocytosis resulting in down regulation of the receptor and eventually the signaling cascade. [7] The molecular mechanism involves the engulfing of the RTK by a clathrin-mediated endocytosis leading to intracellular degradation.[7]
Drug Therapy
editRTKs have become an attractive target for drug therapy due to their implication in a variety of cellular abnormalities such as cancer, degenerative diseases and cardiovascular diseases. The United States Food and Drug Administration (FDA) has approved several anti-cancer drugs caused by activated RTKs. Drugs have been developed to target the extracellular domain or the catalytic domain, thus inhibiting ligand binding, receptor oligomerization.[8] Heceptin, a monoclonal antibody that is capable of binding to the extracellular domain of RTKs, has be used to treat HER2 overexpression in breast cancer. [9]
| Small Molecule | Target | Disease | Approval Year |
|---|---|---|---|
| Imatinib (Gleevec) | PDGFR, KIT, Abl, Arg | SML, GIST | 2001 |
| Gefitinib (Iressa) | EGFR | Esophageal cancer, Glioma | 2003 |
| Erlotinib (Tarceva) | EGFR | Esophageal cancer, Glioma | 2004 |
| Sorafenib (Nexavar) | Raf, VEGFR, PDGFR, Flt3, KIT | Renal cell carcinoma | 2005 |
| Sunitinib (Sutent) | KIT, VEGFR, PDGFR, Flt3 | Renal cell carcinoma, GIST, Endocrine pancreatic cancer | 2006 |
| Desatinib (Sprycel) | Abl, Arg, KIT, PDGFR, Src | Gleevec-resistant CML | 2007 |
| Nilotinib (Tasigna) | Abl, Arg, KIT, PDGFR | Gleevec-resistant CML | 2007 |
| Lapatinib (Tykerb) | EGFR, ErbB2 | Mammary carcinoma | 2007 |
| Trastuzumab (Herceptin) | ErbB2 | Mammary carcinoma | 1998 |
| Cetuximab (Erbitux) | EGFR | Colorectal cancer, Head and neck cancer | 2004 |
| Bevacizumab (Avastin) | VEGF | Lung cancer, Colorectal cancer | 2004 |
| Panitumumab (Vectibix) | EGFR | Colorectal cancer | 2006 |
+ Table adapted fro "Cell signalling by recptor-tyrosine kinases," by Lemmon and Schlessinger's, 2010. Cell, 141, p. 1117–1134.
- ^ Haj, Fawaz G.; Markova, Boyka; Klaman, Lori D.; Bohmer, Frank D.; Neel, Benjamin G. (2003-01-10). "Regulation of Receptor Tyrosine Kinase Signaling by Protein Tyrosine Phosphatase-1B". Journal of Biological Chemistry. 278 (2): 739–744. doi:10.1074/jbc.M210194200. ISSN 0021-9258. PMID 12424235.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Volinsky, Natalia; Kholodenko, Boris N. (2017-03-15). "Complexity of Receptor Tyrosine Kinase Signal Processing". Cold Spring Harbor Perspectives in Biology. 5 (8). doi:10.1101/cshperspect.a009043. ISSN 1943-0264. PMC 3721286. PMID 23906711.
- ^ Hermiston, Michelle L.; Zikherman, Julie; Zhu, Jing W. (2017-03-15). "CD45, CD148, and Lyp/Pep: Critical Phosphatases Regulating Src Family Kinase Signaling Networks in Immune Cells". Immunological reviews. 228 (1): 288–311. doi:10.1111/j.1600-065X.2008.00752.x. ISSN 0105-2896. PMC 2739744. PMID 19290935.
- ^ "Herstatin, an Autoinhibitor of the Human Epidermal Growth Factor Receptor 2 Tyrosine Kinase, Modulates Epidermal Growth Factor Signaling Pathways Resulting in Growth Arrest". PubMed Journals. Retrieved 2017-03-15.
- ^ Ledda, Fernanda; Paratcha, Gustavo (2007-02-14). "Negative Regulation of Receptor Tyrosine Kinase (RTK) Signaling: A Developing Field". Biomarker Insights. 2: 45–58. ISSN 1177-2719. PMC 2717834. PMID 19662191.
- ^ Azios, N. G.; Romero, F. J.; Denton, M. C.; Doherty, J. K.; Clinton, G. M. (2001-08-23). "Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor". Oncogene. 20 (37): 5199–5209. doi:10.1038/sj.onc.1204555. ISSN 0950-9232. PMID 11526509.
- ^ a b Lemmon, Mark A.; Schlessinger, Joseph (2010-06-25). "Cell signaling by receptor tyrosine kinases". Cell. 141 (7): 1117–1134. doi:10.1016/j.cell.2010.06.011. ISSN 1097-4172. PMC 2914105. PMID 20602996.
- ^ Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P.; Haridas, Dhanya; Jain, Maneesh; Ganti, AparK.; Batra, Surinder K. (2017-03-15). "Targeting the EGFR signaling pathway in cancer therapy". Expert Opinion on Therapeutic Targets. 16 (1): 15–31. doi:10.1517/14728222.2011.648617. ISSN 1472-8222. PMC 3291787. PMID 22239438.
- ^ Carlsson, J; Nordgren, H; Sjöström, J; Wester, K; Villman, K; Bengtsson, N O; Ostenstad, B; Lundqvist, H; Blomqvist, C (2004-06-14). "HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review". British Journal of Cancer. 90 (12): 2344–2348. doi:10.1038/sj.bjc.6601881. ISSN 0007-0920. PMC 2409528. PMID 15150568.
- ^ Lemmon, Mark A.; Schlessinger, Joseph (2010-06-25). "Cell signaling by receptor-tyrosine kinases". Cell. 141 (7): 1117–1134. doi:10.1016/j.cell.2010.06.011. ISSN 0092-8674. PMC 2914105. PMID 20602996.