STK11 explained

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.^[1]

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.^[2]

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.^[3]

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.^{[4] [5]} 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.^[6]

Loss of LKB1 activity is associated with highly aggressive HER2+ breast cancer.^[7] 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.^[8] 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.^[9]

Clinical significance

At least 51 disease-causing mutations in this gene have been discovered.^[10] 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.^{[11] [12] [13]} However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas.^[14] 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.^{[15] [16]}

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.^[17]

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.^[18]

Structure

The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography,^[19] 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).^{[20] [21]} The short LKB1 variant is predominantly found in testes.

Interactions

STK11 has been shown to interact with:

• CDC37,^[22]
• * FYN^[23]
• HSP90AA1^[22]
• LYK5^{[24] [25]}
• SMARCA4^[26]
• ESR1^[27]

Further reading

• Yoo LI, Chung DC, Yuan J . LKB1--a master tumour suppressor of the small intestine and beyond . Nature Reviews. Cancer . 2 . 7 . 529–35 . July 2002 . 12094239 . 10.1038/nrc843 . 43512220 .
• Baas AF, Smit L, Clevers H . LKB1 tumor suppressor protein: PARtaker in cell polarity . Trends in Cell Biology . 14 . 6 . 312–9 . June 2004 . 15183188 . 10.1016/j.tcb.2004.04.001 .
• Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP . The LKB1 tumor suppressor kinase in human disease . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1775 . 1 . 63–75 . January 2007 . 17010524 . 10.1016/j.bbcan.2006.08.003 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Bignell GR, Barfoot R, Seal S, Collins N, Warren W, Stratton MR . Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer . Cancer Research . 58 . 7 . 1384–6 . April 1998 . 9537235 .
• Nakagawa H, Koyama K, Miyoshi Y, Ando H, Baba S, Watatani M, Yasutomi M, Matsuura N, Monden M, Nakamura Y . 6 . Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome . Human Genetics . 103 . 2 . 168–72 . August 1998 . 9760200 . 10.1007/s004390050801 . 23986504 .
• Mehenni H, Gehrig C, Nezu J, Oku A, Shimane M, Rossier C, Guex N, Blouin JL, Scott HS, Antonarakis SE . 6 . 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 . December 1998 . 9837816 . 1377635 . 10.1086/302159 .
• Guldberg P, thor Straten P, Ahrenkiel V, Seremet T, Kirkin AF, Zeuthen J . Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma . Oncogene . 18 . 9 . 1777–80 . March 1999 . 10208439 . 10.1038/sj.onc.1202486 . free .
• Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern SE . 6 . 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 . June 1999 . 10362809 . 1866632 . 10.1016/S0002-9440(10)65440-5 .
• Westerman AM, Entius MM, Boor PP, Koole R, de Baar E, Offerhaus GJ, Lubinski J, Lindhout D, Halley DJ, de Rooij FW, Wilson JH . 6 . Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families . Human Mutation . 13 . 6 . 476–81 . 1999 . 10408777 . 10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2 . 27714949 . free .
• Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ . 6 . Antigens recognized by autologous antibody in patients with renal-cell carcinoma . International Journal of Cancer . 83 . 4 . 456–64 . November 1999 . 10508479 . 10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5 . free .
• Collins SP, Reoma JL, Gamm DM, Uhler MD . 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 . February 2000 . 10642527 . 1220803 . 10.1042/0264-6021:3450673 .
• Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, Morrice N, Deak M, Alessi DR . 6 . 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 . June 2001 . 11297520 . 10.1074/jbc.M009953200 . free .
• Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J . 6 . The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death . Molecular Cell . 7 . 6 . 1307–19 . June 2001 . 11430832 . 10.1016/S1097-2765(01)00258-1 . free .
• Carretero J, Medina PP, Pio R, Montuenga LM, Sanchez-Cespedes M . Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene . Oncogene . 23 . 22 . 4037–40 . May 2004 . 15021901 . 10.1038/sj.onc.1207502 . free . 10171/18813 . free .
• Abed AA, Günther K, Kraus C, Hohenberger W, Ballhausen WG . 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 . November 2001 . 11668633 . 10.1002/humu.1211 . 39255354 . free .
• Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Goggins M . 6 . STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas . The American Journal of Pathology . 159 . 6 . 2017–22 . December 2001 . 11733352 . 1850608 . 10.1016/S0002-9440(10)63053-2 .

External links

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

Notes and References

1. Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Müller O, Back W, Zimmer M . 6 . Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase . Nature Genetics . 18 . 1 . 38–43 . January 1998 . 9425897 . 10.1038/ng0198-38 . 28986057 .
2. McInnes KJ, Brown KA, Hunger NI, Simpson ER . Regulation of LKB1 expression by sex hormones in adipocytes . International Journal of Obesity . 36 . 7 . 982–5 . July 2012 . 21876548 . 10.1038/ijo.2011.172 . free .
3. Brown KA, McInnes KJ, Takagi K, Ono K, Hunger NI, Wang L, Sasano H, Simpson ER . 6 . LKB1 expression is inhibited by estradiol-17β in MCF-7 cells . The Journal of Steroid Biochemistry and Molecular Biology . 127 . 3–5 . 439–43 . November 2011 . 21689749 . 10.1016/j.jsbmb.2011.06.005 . 25221068 .
4. Baas . Annette F . Smit . Linda . Clevers . Hans . June 2004 . LKB1 tumor suppressor protein: PARtaker in cell polarity . Trends in Cell Biology . en . 14 . 6 . 312–319 . 10.1016/j.tcb.2004.04.001. 15183188 .
5. Partanen . Johanna I. . Tervonen . Topi A. . Klefström . Juha . 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 . en . 368 . 1629 . 20130111 . 10.1098/rstb.2013.0111 . 0962-8436 . 3785967 . 24062587.
6. Qu . Shuang . Liao . Qiao . Yu . Cheng . Chen . Yue . Luo . Han . Xia . Xuewei . He . Duofen . Xu . Zaicheng . Jose . Pedro A. . Li . Zhuxin . Wang . Wei Eric . 2022-05-25 . LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis . Bosnian Journal of Basic Medical Sciences . 22 . 5 . 772–783 . en . 10.17305/bjbms.2021.7225 . 35490365 . 248465561 . 1840-4812. free . 9519156 .
7. Andrade-Vieira R, Xu Z, Colp P, Marignani PA . Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways . PLOS ONE . 8 . 2 . e56567 . 2013-02-22 . 23451056 . 3579833 . 10.1371/journal.pone.0056567 . 2013PLoSO...856567A . free .
8. Andrade-Vieira R, Goguen D, Bentley HA, Bowen CV, Marignani PA . 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 . December 2014 . 25436981 . 4350354 . 10.18632/oncotarget.2818 .
9. Scott KD, Nath-Sain S, Agnew MD, Marignani PA . LKB1 catalytically deficient mutants enhance cyclin D1 expression . Cancer Research . 67 . 12 . 5622–7 . June 2007 . 17575127 . 10.1158/0008-5472.CAN-07-0762 . free .
10. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
11. Hemminki A, Tomlinson I, Markie D, Järvinen H, Sistonen P, Björkqvist AM, Knuutila S, Salovaara R, Bodmer W, Shibata D, de la Chapelle A, Aaltonen LA . 6 . 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 . January 1997 . 8988175 . 10.1038/ng0197-87 . 8978401 .
12. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Höglund P, Järvinen H, Kristo P, Pelin K, Ridanpää M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA . 6 . A serine/threonine kinase gene defective in Peutz-Jeghers syndrome . Nature . 391 . 6663 . 184–7 . January 1998 . 9428765 . 10.1038/34432 . 1998Natur.391..184H . 4400728 .
13. Scott R, Crooks R, Meldrum C . Gene symbol: STK11. Disease: Peutz-Jeghers Syndrome . Human Genetics . 124 . 3 . 300 . October 2008 . 18846624 . 10.1007/s00439-008-0551-3 .
14. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, Westra WH, Herman JG, Sidransky D . 6 . Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung . Cancer Research . 62 . 13 . 3659–62 . July 2002 . 12097271 . James G. Herman .
15. Sanchez-Cespedes M . A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome . Oncogene . 26 . 57 . 7825–32 . December 2007 . 17599048 . 10.1038/sj.onc.1210594 . free .
16. Web site: Distribution of somatic mutations in STK11 . Catalogue of Somatic Mutations in Cancer . Wellcome Trust Genome Campus, Hinxton, Cambridge . 2009-11-11 . 2012-04-02 . https://web.archive.org/web/20120402153613/http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=STK11&start=1&end=434&coords=AA:AA . dead .
17. Qu . Shuang . Liao . Qiao . Yu . Cheng . Chen . Yue . Luo . Han . Xia . Xuewei . He . Duofen . Xu . Zaicheng . Jose . Pedro A. . Li . Zhuxin . Wang . Wei Eric . 2022-05-25 . LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis . Bosnian Journal of Basic Medical Sciences . 22 . 5 . 772–783 . en . 10.17305/bjbms.2021.7225 . 35490365 . 248465561 . 1840-4812. free . 9519156 .
18. Marignani PA, Scott KD, Bagnulo R, Cannone D, Ferrari E, Stella A, Guanti G, Simone C, Resta N . 6 . Novel splice isoforms of STRADalpha differentially affect LKB1 activity, complex assembly and subcellular localization . Cancer Biology & Therapy . 6 . 10 . 1627–31 . October 2007 . 17921699 . 10.4161/cbt.6.10.4787 . free .

19. Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM . Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation . Science . 326 . 5960 . 1707–11 . December 2009 . 19892943 . 3518268 . 10.1126/science.1178377 . 2009Sci...326.1707Z .

20. Towler . Mhairi C. . Fogarty . Sarah . Hawley . Simon A. . Pan . David A. . Martin . David M. A. . Morrice . Nicolas A. . McCarthy . Afshan . Galardo . María N. . Meroni . Silvina B. . Cigorraga . Selva B. . Ashworth . Alan . Sakamoto . Kei . Hardie . D. Grahame . 2008-11-15 . A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis . Biochemical Journal . en . 416 . 1 . 1–14 . 10.1042/BJ20081447 . 18774945 . 0264-6021.
21. Denison . Fiona C. . Hiscock . Natalie J. . Carling . David . Woods . Angela . 2009-01-02 . Characterization of an Alternative Splice Variant of LKB1 . Journal of Biological Chemistry . en . 284 . 1 . 67–76 . 10.1074/jbc.M806153200. free . 18854309 .
22. Boudeau J, Deak M, Lawlor MA, Morrice NA, Alessi DR . Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability . The Biochemical Journal . 370 . Pt 3 . 849–57 . March 2003 . 12489981 . 1223241 . 10.1042/BJ20021813 .
23. Yamada E, Bastie CC . 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 . February 2014 . 24586906 . 3934923 . 10.1371/journal.pone.0089604 . 2014PLoSO...989604Y . free .
24. Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D, Hardie DG, Prescott AR, van Aalten DM, Alessi DR . 6 . Analysis of the LKB1-STRAD-MO25 complex . Journal of Cell Science . 117 . Pt 26 . 6365–75 . December 2004 . 15561763 . 10.1242/jcs.01571 . free .
25. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC . 6 . Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD . The EMBO Journal . 22 . 12 . 3062–72 . June 2003 . 12805220 . 162144 . 10.1093/emboj/cdg292 .
26. Marignani PA, Kanai F, Carpenter CL . LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest . The Journal of Biological Chemistry . 276 . 35 . 32415–8 . August 2001 . 11445556 . 10.1074/jbc.C100207200 . free .
27. Nath-Sain S, Marignani PA . LKB1 catalytic activity contributes to estrogen receptor alpha signaling . Molecular Biology of the Cell . 20 . 11 . 2785–95 . June 2009 . 19369417 . 2688557 . 10.1091/mbc.e08-11-1138 .