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STK11

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STK11
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSTK11, LKB1, PJS, hLKB1, serine/threonine kinase 11
External IDsOMIM: 602216; MGI: 1341870; HomoloGene: 393; GeneCards: STK11; OMA:STK11 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 10: 79.95 – 79.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

Expression

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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.[6]

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.[7]

Function

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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.[8][9] 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.[10]

Loss of LKB1 activity is associated with highly aggressive HER2+ breast cancer.[11] 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.[12] 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.[13]

Clinical significance

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At least 51 disease-causing mutations in this gene have been discovered.[14] 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.[15][16][17] However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas.[18] Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast,[11] intestinal, testicular, pancreatic and skin cancer.[19][20]

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.[21]

Activation

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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.[22]

Structure

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The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography,[23] 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

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Alternate transcriptional splice variants of this gene have been observed and characterized. There are two main splice isoforms denoted LKB1 long (LKB1L) and LKB1 short (LKB1S).[24][25] The short LKB1 variant is predominantly found in testes.

Interactions

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STK11 has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000118046 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000003068 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, et al. (January 1998). "Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase". Nature Genetics. 18 (1): 38–43. doi:10.1038/ng0198-38. PMID 9425897. S2CID 28986057.
  6. ^ McInnes KJ, Brown KA, Hunger NI, Simpson ER (July 2012). "Regulation of LKB1 expression by sex hormones in adipocytes". International Journal of Obesity. 36 (7): 982–5. doi:10.1038/ijo.2011.172. PMID 21876548.
  7. ^ Brown KA, McInnes KJ, Takagi K, Ono K, Hunger NI, Wang L, et al. (November 2011). "LKB1 expression is inhibited by estradiol-17β in MCF-7 cells". The Journal of Steroid Biochemistry and Molecular Biology. 127 (3–5): 439–43. doi:10.1016/j.jsbmb.2011.06.005. PMID 21689749. S2CID 25221068.
  8. ^ Baas AF, Smit L, Clevers H (June 2004). "LKB1 tumor suppressor protein: PARtaker in cell polarity". Trends in Cell Biology. 14 (6): 312–319. doi:10.1016/j.tcb.2004.04.001. PMID 15183188.
  9. ^ Partanen JI, Tervonen TA, Klefström J (2013-11-05). "Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4". Philosophical Transactions of the Royal Society B: Biological Sciences. 368 (1629): 20130111. doi:10.1098/rstb.2013.0111. ISSN 0962-8436. PMC 3785967. PMID 24062587.
  10. ^ Qu S, Liao Q, Yu C, Chen Y, Luo H, Xia X, He D, Xu Z, Jose PA, Li Z, Wang WE (2022-05-25). "LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis". Bosnian Journal of Basic Medical Sciences. 22 (5): 772–783. doi:10.17305/bjbms.2021.7225. ISSN 1840-4812. PMC 9519156. PMID 35490365. S2CID 248465561.
  11. ^ a b Andrade-Vieira R, Xu Z, Colp P, Marignani PA (2013-02-22). "Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways". PLOS ONE. 8 (2): e56567. Bibcode:2013PLoSO...856567A. doi:10.1371/journal.pone.0056567. PMC 3579833. PMID 23451056.
  12. ^ Andrade-Vieira R, Goguen D, Bentley HA, Bowen CV, Marignani PA (December 2014). "Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss". Oncotarget. 5 (24): 12738–52. doi:10.18632/oncotarget.2818. PMC 4350354. PMID 25436981.
  13. ^ Scott KD, Nath-Sain S, Agnew MD, Marignani PA (June 2007). "LKB1 catalytically deficient mutants enhance cyclin D1 expression". Cancer Research. 67 (12): 5622–7. doi:10.1158/0008-5472.CAN-07-0762. PMID 17575127.
  14. ^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
  15. ^ Hemminki A, Tomlinson I, Markie D, Järvinen H, Sistonen P, Björkqvist AM, et al. (January 1997). "Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis". Nature Genetics. 15 (1): 87–90. doi:10.1038/ng0197-87. PMID 8988175. S2CID 8978401.
  16. ^ Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, et al. (January 1998). "A serine/threonine kinase gene defective in Peutz-Jeghers syndrome". Nature. 391 (6663): 184–7. Bibcode:1998Natur.391..184H. doi:10.1038/34432. PMID 9428765. S2CID 4400728.
  17. ^ Scott R, Crooks R, Meldrum C (October 2008). "Gene symbol: STK11. Disease: Peutz-Jeghers Syndrome". Human Genetics. 124 (3): 300. doi:10.1007/s00439-008-0551-3. PMID 18846624.
  18. ^ Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, et al. (July 2002). "Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung". Cancer Research. 62 (13): 3659–62. PMID 12097271.
  19. ^ Sanchez-Cespedes M (December 2007). "A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome". Oncogene. 26 (57): 7825–32. doi:10.1038/sj.onc.1210594. PMID 17599048.
  20. ^ "Distribution of somatic mutations in STK11". Catalogue of Somatic Mutations in Cancer. Wellcome Trust Genome Campus, Hinxton, Cambridge. Archived from the original on 2012-04-02. Retrieved 2009-11-11.
  21. ^ Qu S, Liao Q, Yu C, Chen Y, Luo H, Xia X, He D, Xu Z, Jose PA, Li Z, Wang WE (2022-05-25). "LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis". Bosnian Journal of Basic Medical Sciences. 22 (5): 772–783. doi:10.17305/bjbms.2021.7225. ISSN 1840-4812. PMC 9519156. PMID 35490365. S2CID 248465561.
  22. ^ Marignani PA, Scott KD, Bagnulo R, Cannone D, Ferrari E, Stella A, et al. (October 2007). "Novel splice isoforms of STRADalpha differentially affect LKB1 activity, complex assembly and subcellular localization". Cancer Biology & Therapy. 6 (10): 1627–31. doi:10.4161/cbt.6.10.4787. PMID 17921699.
  23. ^ PDB: 2WTK​; Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM (December 2009). "Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation". Science. 326 (5960): 1707–11. Bibcode:2009Sci...326.1707Z. doi:10.1126/science.1178377. PMC 3518268. PMID 19892943.
  24. ^ Towler MC, Fogarty S, Hawley SA, Pan DA, Martin DM, Morrice NA, McCarthy A, Galardo MN, Meroni SB, Cigorraga SB, Ashworth A, Sakamoto K, Hardie DG (2008-11-15). "A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis". Biochemical Journal. 416 (1): 1–14. doi:10.1042/BJ20081447. ISSN 0264-6021. PMID 18774945.
  25. ^ Denison FC, Hiscock NJ, Carling D, Woods A (2009-01-02). "Characterization of an Alternative Splice Variant of LKB1". Journal of Biological Chemistry. 284 (1): 67–76. doi:10.1074/jbc.M806153200. PMID 18854309.
  26. ^ a b Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR (March 2003). "Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability". The Biochemical Journal. 370 (Pt 3): 849–57. doi:10.1042/BJ20021813. PMC 1223241. PMID 12489981.
  27. ^ Yamada E, Bastie CC (February 2014). "Disruption of Fyn SH3 domain interaction with a proline-rich motif in liver kinase B1 results in activation of AMP-activated protein kinase". PLOS ONE. 9 (2): e89604. Bibcode:2014PLoSO...989604Y. doi:10.1371/journal.pone.0089604. PMC 3934923. PMID 24586906.
  28. ^ Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D, et al. (December 2004). "Analysis of the LKB1-STRAD-MO25 complex". Journal of Cell Science. 117 (Pt 26): 6365–75. doi:10.1242/jcs.01571. PMID 15561763.
  29. ^ Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, et al. (June 2003). "Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD". The EMBO Journal. 22 (12): 3062–72. doi:10.1093/emboj/cdg292. PMC 162144. PMID 12805220.
  30. ^ Marignani PA, Kanai F, Carpenter CL (August 2001). "LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest". The Journal of Biological Chemistry. 276 (35): 32415–8. doi:10.1074/jbc.C100207200. PMID 11445556.
  31. ^ Nath-Sain S, Marignani PA (June 2009). "LKB1 catalytic activity contributes to estrogen receptor alpha signaling". Molecular Biology of the Cell. 20 (11): 2785–95. doi:10.1091/mbc.e08-11-1138. PMC 2688557. PMID 19369417.

Further reading

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


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