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STK11  -  serine/threonine kinase 11

Homo sapiens

 
 
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Disease relevance of STK11

 

High impact information on STK11

  • We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25) [6].
  • The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels [6].
  • The LKB1 gene encodes a serine/threonine kinase that is mutated in the Peutz-Jeghers cancer syndrome [7].
  • Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD [7].
  • LKB1 is homologous to the Par-4 polarity genes in C. elegans and D. melanogaster [7].
 

Chemical compound and disease context of STK11

 

Biological context of STK11

 

Anatomical context of STK11

 

Associations of STK11 with chemical compounds

  • A serine threonine kinase gene, STK11, has been identified as the tumor suppressor gene responsible for the PJS [15].
  • However, nonsense mediated mRNA decay must be blocked with puromycin to detect shortened STK11 gene products contained in the leucocytic mRNA pool of PJS patients [18].
  • Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases [19].
  • LKB1 is a serine/threonine kinase which is inactivated by mutation in the Peutz-Jeghers polyposis and cancer predisposition syndrome (PJS) [20].
  • The endocrine tumors of CS and PJS, which could classify these disorders as variant types of multiple endocrine neoplasias (MENs), are not present in most CS and BRR patients, but lentigines are shared by PJS, CNC and BRR [9].
  • We also demonstrate that LKB1 wild-type cells are more resistant to cell death upon glucose withdrawal than their mutant counterparts [21].
  • We conclude that PKCzeta mediates LKB1-dependent Akt inhibition in response to ONOO(-), resulting in endothelial apoptosis [22].
 

Physical interactions of STK11

 

Enzymatic interactions of STK11

  • LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes [13].
  • We demonstrate that both DNA-PK and ATM efficiently phosphorylate LKB1 at Thr-366 in vitro and provide evidence that ATM mediates this phosphorylation in vivo [27].
  • Recent work has shown that the LKB1 tumour suppressor protein kinase phosphorylates and activates protein kinases belonging to the AMP activated kinase (AMPK) subfamily [28].
 

Regulatory relationships of STK11

  • LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1 [19].
  • This suggests that LKB1-induced apoptosis is p53 independent but might be p73-mediated in the pancreatic tumor cell line, AsPC-1 [29].
  • Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1 [30].
  • BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells [31].
  • Ectopic expression of cyclooxygenase-2 and endogenous biosynthesis of eicosanoids also inhibited LKB1 activity in MCF-7 cells [32].
  • These results suggest that LKB1 deacetylation is regulated by SIRT1 and that this in turn influences its intracellular localization, association with STRAD, kinase activity, and ability to activate AMPK [33].
 

Other interactions of STK11

  • Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome [34].
  • LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation [19].
  • Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold [19].
  • Several LKB1 point mutations associated with PJS disrupt the interaction with PTEN suggesting that the loss of this interaction might contribute to PJS [13].
  • LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1 [20].
  • Conditional LKB1 mouse models have outlined a tissue-dependent context for pathway activation and suggest that LKB1 may affect different AMPK isoforms independently [35].
 

Analytical, diagnostic and therapeutic context of STK11

References

  1. Relative frequency and morphology of cancers in STK11 mutation carriers. Lim, W., Olschwang, S., Keller, J.J., Westerman, A.M., Menko, F.H., Boardman, L.A., Scott, R.J., Trimbath, J., Giardiello, F.M., Gruber, S.B., Gille, J.J., Offerhaus, G.J., de Rooij, F.W., Wilson, J.H., Spigelman, A.D., Phillips, R.K., Houlston, R.S. Gastroenterology (2004) [Pubmed]
  2. Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Gruber, S.B., Entius, M.M., Petersen, G.M., Laken, S.J., Longo, P.A., Boyer, R., Levin, A.M., Mujumdar, U.J., Trent, J.M., Kinzler, K.W., Vogelstein, B., Hamilton, S.R., Polymeropoulos, M.H., Offerhaus, G.J., Giardiello, F.M. Cancer Res. (1998) [Pubmed]
  3. Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma. Guldberg, P., thor Straten, P., Ahrenkiel, V., Seremet, T., Kirkin, A.F., Zeuthen, J. Oncogene (1999) [Pubmed]
  4. Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases. Hearle, N., Lucassen, A., Wang, R., Lim, W., Ross, F., Wheeler, R., Moore, I., Shipley, J., Houlston, R. Genes Chromosomes Cancer (2004) [Pubmed]
  5. Progress in cancer genetics: lessons from pancreatic cancer. Goggins, M., Kern, S.E., Offerhaus, J.A., Hruban, R.H. Ann. Oncol. (1999) [Pubmed]
  6. Lkb1-dependent signaling pathways. Alessi, D.R., Sakamoto, K., Bayascas, J.R. Annu. Rev. Biochem. (2006) [Pubmed]
  7. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Baas, A.F., Kuipers, J., van der Wel, N.N., Batlle, E., Koerten, H.K., Peters, P.J., Clevers, H.C. Cell (2004) [Pubmed]
  8. Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. Boudeau, J., Kieloch, A., Alessi, D.R., Stella, A., Guanti, G., Resta, N. Hum. Mutat. (2003) [Pubmed]
  9. Genetics of Peutz-Jeghers syndrome, Carney complex and other familial lentiginoses. Stratakis, C.A. Horm. Res. (2000) [Pubmed]
  10. Growth and molecular profile of lung cancer cells expressing ectopic LKB1: down-regulation of the phosphatidylinositol 3'-phosphate kinase/PTEN pathway. Jimenez, A.I., Fernandez, P., Dominguez, O., Dopazo, A., Sanchez-Cespedes, M. Cancer Res. (2003) [Pubmed]
  11. Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. Nony, P., Gaude, H., Rossel, M., Fournier, L., Rouault, J.P., Billaud, M. Oncogene (2003) [Pubmed]
  12. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Jenne, D.E., Reimann, H., Nezu, J., Friedel, W., Loff, S., Jeschke, R., Müller, O., Back, W., Zimmer, M. Nat. Genet. (1998) [Pubmed]
  13. LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Mehenni, H., Lin-Marq, N., Buchet-Poyau, K., Reymond, A., Collart, M.A., Picard, D., Antonarakis, S.E. Hum. Mol. Genet. (2005) [Pubmed]
  14. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Sanchez-Cespedes, M., Parrella, P., Esteller, M., Nomoto, S., Trink, B., Engles, J.M., Westra, W.H., Herman, J.G., Sidransky, D. Cancer Res. (2002) [Pubmed]
  15. Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix. Kuragaki, C., Enomoto, T., Ueno, Y., Sun, H., Fujita, M., Nakashima, R., Ueda, Y., Wada, H., Murata, Y., Toki, T., Konishi, I., Fujii, S. Lab. Invest. (2003) [Pubmed]
  16. Genetic pathways of colorectal carcinogenesis rarely involve the PTEN and LKB1 genes outside the inherited hamartoma syndromes. Wang, Z.J., Taylor, F., Churchman, M., Norbury, G., Tomlinson, I. Am. J. Pathol. (1998) [Pubmed]
  17. 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. Sapkota, G.P., Kieloch, A., Lizcano, J.M., Lain, S., Arthur, J.S., Williams, M.R., Morrice, N., Deak, M., Alessi, D.R. J. Biol. Chem. (2001) [Pubmed]
  18. 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). Abed, A.A., Günther, K., Kraus, C., Hohenberger, W., Ballhausen, W.G. Hum. Mutat. (2001) [Pubmed]
  19. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. Lizcano, J.M., Göransson, O., Toth, R., Deak, M., Morrice, N.A., Boudeau, J., Hawley, S.A., Udd, L., Mäkelä, T.P., Hardie, D.G., Alessi, D.R. EMBO J. (2004) [Pubmed]
  20. LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. Smith, D.P., Rayter, S.I., Niederlander, C., Spicer, J., Jones, C.M., Ashworth, A. Hum. Mol. Genet. (2001) [Pubmed]
  21. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Carretero, J., Medina, P.P., Blanco, R., Smit, L., Tang, M., Roncador, G., Maestre, L., Conde, E., Lopez-Rios, F., Clevers, H.C., Sanchez-Cespedes, M. Oncogene (2007) [Pubmed]
  22. Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. Song, P., Xie, Z., Wu, Y., Xu, J., Dong, Y., Zou, M.H. J. Biol. Chem. (2008) [Pubmed]
  23. Analysis of the LKB1-STRAD-MO25 complex. Boudeau, J., Scott, J.W., Resta, N., Deak, M., Kieloch, A., Komander, D., Hardie, D.G., Prescott, A.R., van Aalten, D.M., Alessi, D.R. J. Cell. Sci. (2004) [Pubmed]
  24. LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. Marignani, P.A., Kanai, F., Carpenter, C.L. J. Biol. Chem. (2001) [Pubmed]
  25. Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability. Boudeau, J., Deak, M., Lawlor, M.A., Morrice, N.A., Alessi, D.R. Biochem. J. (2003) [Pubmed]
  26. LKB1/STK11 Suppresses Cyclooxygenase-2 Induction and Cellular Invasion through PEA3 in Lung Cancer. Upadhyay, S., Liu, C., Chatterjee, A., Hoque, M.O., Kim, M.S., Engles, J., Westra, W., Trink, B., Ratovitski, E., Sidransky, D. Cancer Res. (2006) [Pubmed]
  27. Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. Sapkota, G.P., Deak, M., Kieloch, A., Morrice, N., Goodarzi, A.A., Smythe, C., Shiloh, Y., Lees-Miller, S.P., Alessi, D.R. Biochem. J. (2002) [Pubmed]
  28. Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. Jaleel, M., McBride, A., Lizcano, J.M., Deak, M., Toth, R., Morrice, N.A., Alessi, D.R. FEBS Lett. (2005) [Pubmed]
  29. Restoration of silenced Peutz-Jeghers syndrome gene, LKB1, induces apoptosis in pancreatic carcinoma cells. Qanungo, S., Haldar, S., Basu, A. Neoplasia (2003) [Pubmed]
  30. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. Baas, A.F., Boudeau, J., Sapkota, G.P., Smit, L., Medema, R., Morrice, N.A., Alessi, D.R., Clevers, H.C. EMBO J. (2003) [Pubmed]
  31. BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Sapkota, G.P., Cummings, L., Newell, F.S., Armstrong, C., Bain, J., Frodin, M., Grauert, M., Hoffmann, M., Schnapp, G., Steegmaier, M., Cohen, P., Alessi, D.R. Biochem. J. (2007) [Pubmed]
  32. Reactive lipid species from cyclooxygenase-2 inactivate tumor suppressor LKB1/STK11: cyclopentenone prostaglandins and 4-hydroxy-2-nonenal covalently modify and inhibit the AMP-kinase kinase that modulates cellular energy homeostasis and protein translation. Wagner, T.M., Mullally, J.E., Fitzpatrick, F.A. J. Biol. Chem. (2006) [Pubmed]
  33. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. Lan, F., Cacicedo, J.M., Ruderman, N., Ido, Y. J. Biol. Chem. (2008) [Pubmed]
  34. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Corradetti, M.N., Inoki, K., Bardeesy, N., DePinho, R.A., Guan, K.L. Genes Dev. (2004) [Pubmed]
  35. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Jansen, M., Ten Klooster, J.P., Offerhaus, G.J., Clevers, H. Physiol. Rev. (2009) [Pubmed]
 
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