STK11

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.

STK11
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2WTK, 4ZDR
Identifiers
Aliases	STK11, LKB1, PJS, hLKB1, serine/threonine kinase 11
External IDs	OMIM: 602216; MGI: 1341870; HomoloGene: 393; GeneCards: STK11; OMA:STK11 - orthologs
Gene location (Human) Chr. Chromosome 19 (human) Band 19p13.3 Start 1,177,558 bp End 1,228,431 bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10|10 C1 Start 79,951,637 bp End 79,966,516 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left testis right testis muscle of thigh gastrocnemius muscle granulocyte stromal cell of endometrium right hemisphere of cerebellum tendon of biceps brachii mucosa of transverse colon apex of heart Top expressed in Ileal epithelium granulocyte saccule ventricular zone muscle of thigh otic placode neural layer of retina lip zygote yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding LRR domain binding protein kinase activity p53 binding protein kinase activator activity metal ion binding kinase activity protein serine/threonine kinase activity protein binding ATP binding magnesium ion binding Cellular component cytoplasm membrane mitochondrion extracellular exosome TCR signalosome nucleus nucleoplasm cytosol Biological process response to ionizing radiation positive regulation of transforming growth factor beta receptor signaling pathway dendrite extension TCR signalosome assembly axonogenesis glucose homeostasis positive regulation of autophagy phosphorylation negative regulation of lipid biosynthetic process positive regulation of axonogenesis cellular response to DNA damage stimulus regulation of dendrite morphogenesis autophagy protein phosphorylation Golgi localization regulation of Wnt signaling pathway vasculature development anoikis cellular response to UV-B negative regulation of cell growth regulation of cell growth tissue homeostasis establishment of cell polarity positive thymic T cell selection positive regulation of peptidyl-tyrosine phosphorylation regulation of protein kinase B signaling canonical Wnt signaling pathway intrinsic apoptotic signaling pathway by p53 class mediator protein autophosphorylation cell cycle negative regulation of epithelial cell proliferation involved in prostate gland development T cell receptor signaling pathway spermatogenesis activation of protein kinase activity negative regulation of TORC1 signaling negative regulation of cell population proliferation positive regulation of protein localization to nucleus apoptotic process regulation of signal transduction by p53 class mediator nervous system development peptidyl-serine phosphorylation peptidyl-threonine phosphorylation cell differentiation positive regulation of protein serine/threonine kinase activity protein dephosphorylation negative regulation of canonical Wnt signaling pathway negative regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6794 20869 Ensembl ENSG00000118046 ENSMUSG00000003068 UniProt Q15831 Q9WTK7 RefSeq (mRNA) NM_000455 NM_001301853 NM_001301854 NM_011492 RefSeq (protein) NP_000446 NP_001288782 NP_001288783 NP_035622 Location (UCSC) Chr 19: 1.18 – 1.23 Mb Chr 10: 79.95 – 79.97 Mb PubMed search
Wikidata
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Expression

Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.

However, in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.

Function

The STK11/LKB1 gene, which encodes a member of the serine/threonine kinase family, regulates cell polarity and functions as a tumour suppressor.

LKB1 is a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of ~14 other kinases, comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions. A study in rats showed that LKB1 expression is upregulated in cardiomyocytes after birth and that LKB1 abundance negatively correlates with proliferation of neonatal rat cardiomyocytes.

Loss of LKB1 activity is associated with highly aggressive HER2+ breast cancer. HER2/neu mice were engineered for loss of mammary gland expression of Lkb1 resulting in reduced latency of tumorgenesis. These mice developed mammary tumors that were highly metabolic and hyperactive for MTOR. Pre-clinical studies that simultaneously targeted mTOR and metabolism with AZD8055 (inhibitor of mTORC1 and mTORC2) and 2-DG, respectively inhibited mammary tumors from forming. Mitochondria function In control mice that did not have mammary tumors were not affected by AZD8055/2-DG treatments.

LKB1 catalytic deficient mutants found in Peutz–Jeghers syndrome activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. LKB1 catalytically deficient mutants have oncogenic properties.

Clinical significance

At least 51 disease-causing mutations in this gene have been discovered. Germline mutations in this gene have been associated with Peutz–Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas. Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast, intestinal, testicular, pancreatic and skin cancer.

LKB1 has been implicated as a potential target for inducing cardiac regeneration after injury as the regenerative potential of cardiomyocytes is limited in adult mammals. Knockdown of Lkb1 in rat cardiomyocytes suppressed phosphorylation of AMPK and activated Yes-associated protein, which subsequently promoted cardiomyocyte proliferation.

Activation

LKB1 is activated allosterically by binding to the pseudokinase STRAD and the adaptor protein MO25. The LKB1-STRAD-MO25 heterotrimeric complex represents the biologically active unit, that is capable of phosphorylating and activating AMPK and at least 12 other kinases that belong to the AMPK-related kinase family. Several novel splice isoforms of STRADα that differentially affect LKB1 activity, complex assembly, subcellular localization of LKB1 and the activation of the LKB1-dependent AMPK pathway.

Structure

The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography, and revealed the mechanism by which LKB1 is allosterically activated. LKB1 has a structure typical of other protein kinases, with two (small and large) lobes on either side of the ligand ATP-binding pocket. STRAD and MO25 together cooperate to promote LKB1 active conformation. The LKB1 activation loop, a critical element in the process of kinase activation, is held in place by MO25, thus explaining the huge increase in LKB1 activity in the presence of STRAD and MO25 .

Splice variants

Alternate transcriptional splice variants of this gene have been observed and characterized. There are two main splice isoforms denoted LKB1 long (LKB1_L) and LKB1 short (LKB1_S). The short LKB1 variant is predominantly found in testes.

Interactions

STK11 has been shown to interact with:

• CDC37,
• * FYN
• HSP90AA1
• LYK5
• SMARCA4
• ESR1

See also

• Paola Marignani (living), scientist and university professor, research on tumor suppressor kinase LKB1

Further reading

• Yoo LI, Chung DC, Yuan J (July 2002). "LKB1--a master tumour suppressor of the small intestine and beyond". Nature Reviews. Cancer. 2 (7): 529–35. doi:10.1038/nrc843. PMID 12094239. S2CID 43512220.
• Baas AF, Smit L, Clevers H (June 2004). "LKB1 tumor suppressor protein: PARtaker in cell polarity". Trends in Cell Biology. 14 (6): 312–9. doi:10.1016/j.tcb.2004.04.001. PMID 15183188.
• Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP (January 2007). "The LKB1 tumor suppressor kinase in human disease". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1775 (1): 63–75. doi:10.1016/j.bbcan.2006.08.003. PMID 17010524.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Bignell GR, Barfoot R, Seal S, Collins N, Warren W, Stratton MR (April 1998). "Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer". Cancer Research. 58 (7): 1384–6. PMID 9537235.
• Nakagawa H, Koyama K, Miyoshi Y, Ando H, Baba S, Watatani M, et al. (August 1998). "Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome". Human Genetics. 103 (2): 168–72. doi:10.1007/s004390050801. PMID 9760200. S2CID 23986504.
• Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, et al. (December 1998). "Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity". American Journal of Human Genetics. 63 (6): 1641–50. doi:10.1086/302159. PMC 1377635. PMID 9837816.
• Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J (March 1999). "Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma". Oncogene. 18 (9): 1777–80. doi:10.1038/sj.onc.1202486. PMID 10208439.
• Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, et al. (June 1999). "Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers". The American Journal of Pathology. 154 (6): 1835–40. doi:10.1016/S0002-9440(10)65440-5. PMC 1866632. PMID 10362809.
• Westerman AM, Entius MM, Boor PP, Koole R, de Baar E, Offerhaus GJ, et al. (1999). "Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families". Human Mutation. 13 (6): 476–81. doi:10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2. PMID 10408777. S2CID 27714949.
• Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, et al. (November 1999). "Antigens recognized by autologous antibody in patients with renal-cell carcinoma". International Journal of Cancer. 83 (4): 456–64. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID 10508479.
• Collins SP, Reoma JL, Gamm DM, Uhler MD (February 2000). "LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo". The Biochemical Journal. 345 Pt 3 (3): 673–80. doi:10.1042/0264-6021:3450673. PMC 1220803. PMID 10642527.
• Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, et al. (June 2001). "Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth". The Journal of Biological Chemistry. 276 (22): 19469–82. doi:10.1074/jbc.M009953200. PMID 11297520.
• Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, et al. (June 2001). "The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death". Molecular Cell. 7 (6): 1307–19. doi:10.1016/S1097-2765(01)00258-1. PMID 11430832.
• Carretero J, Medina PP, Pio R, Montuenga LM, Sanchez-Cespedes M (May 2004). "Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene". Oncogene. 23 (22): 4037–40. doi:10.1038/sj.onc.1207502. hdl:10171/18813. PMID 15021901.
• Abed AA, Günther K, Kraus C, Hohenberger W, Ballhausen WG (November 2001). "Mutation screening at the RNA level of the STK11/LKB1 gene in Peutz-Jeghers syndrome reveals complex splicing abnormalities and a novel mRNA isoform (STK11 c.597(insertion mark)598insIVS4)". Human Mutation. 18 (5): 397–410. doi:10.1002/humu.1211. PMID 11668633. S2CID 39255354.
• Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, et al. (December 2001). "STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas". The American Journal of Pathology. 159 (6): 2017–22. doi:10.1016/S0002-9440(10)63053-2. PMC 1850608. PMID 11733352.

External links

• GeneReviews/NCBI/NIH/UW entry on Peutz-Jeghers syndrome
• OMIM entries on Peutz-Jeghers syndrome

This article incorporates text from the United States National Library of Medicine, which is in the public domain.