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LKB1 Is the Upstream Kinase in the AMP-Activated Protein Kinase Cascade

2003; Elsevier BV; Volume: 13; Issue: 22 Linguagem: Inglês

10.1016/j.cub.2003.10.031

1879-0445

Angela Woods, Stephen R. Johnstone, Kristina Dickerson, Fiona C. Leiper, Lee G.D. Fryer, Dietbert Neumann, Uwe Schlattner, Theo Wallimann, Marian Carlson, David Carling,

PI3K/AKT/mTOR signaling in cancer

Inactivating mutations in the protein kinase LKB1 lead to a dominantly inherited cancer in humans termed Peutz-Jeghers syndrome [1Jenne D.E. Reimann H. Nezu J.I. Friedel W. Loff S. Jeschke R. Müller O. Back W. Zimmer M. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Nat. Genet. 1998; 18: 38-43Crossref PubMed Scopus (926) Google Scholar, 2Hemminki A. Markie D. Tomlinson I. Avizienyte E. Roth S. Loukola A. Bignell G. Warren W. Aminoff M. Hoglund P. et al.A serine/threonine kinase gene defective in Peutz–Jeghers syndrome.Nature. 1998; 391: 184-187Crossref PubMed Scopus (1263) Google Scholar]. The role of LKB1 is unclear, and only one target for LKB1 has been identified in vivo [3Baas A.F. Boudeau J. Sapkota G.P. Smit L. Medema R. Morrice N.A. Alessi D.R. Clevers H.C. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.EMBO J. 2003; 22: 3062-3072Crossref PubMed Scopus (281) Google Scholar]. AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a pivotal role in energy homeostasis [4Hardie D.G. Carling D. Carlson M. The AMP-activated/SNF1 protein kinase subfamily metabolic sensors of the eukaryotic cell?.Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1235) Google Scholar]. AMPK may have a role in protecting the body from metabolic diseases including type 2 diabetes [5Winder W.W. Hardie D.G. AMP-activated protein kinase, a metabolic master switch possible roles in type 2 diabetes.Am. J. Physiol. 1999; 277: 1-10PubMed Google Scholar, 6Zhou G. Myers R. Li Y. Chen Y. Shen X. Fenyk-Melody J. Wu M. Ventre J. Doebber T. Fujii N. et al.Role of AMP-activated protein kinase in mechanism of metformin action.J. Clin. Invest. 2001; 108: 1167-1174Crossref PubMed Scopus (4050) Google Scholar], obesity [7Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Leptin stimulates fatty acid oxidation by activating AMP-activated protein kinase.Nature. 2002; 415: 339-343Crossref PubMed Scopus (1600) Google Scholar], and cardiac hypertrophy [8Blair E. Redwood C. Ashrafian H. Ostman-Smith I. Watkins H. Mutations in the γ2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy evidence for the central role of energy compromise in disease pathogenesis.Hum. Mol. Genet. 2001; 10: 1215-1220Crossref PubMed Google Scholar]. We previously reported the identification of three protein kinases (Elm1, Pak1, and Tos3 [9Hong S.P. Leiper F.C. Woods A. Carling D. Carlson M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases.Proc. Natl. Acad. Sci. USA. 2003; 100: 8839-8843Crossref PubMed Scopus (451) Google Scholar]) that lie upstream of Snf1, the yeast homologue of AMPK. LKB1 shares sequence similarity with Elm1, Pak1, and Tos3, and we demonstrated that LKB1 phosphorylates AMPK on the activation loop threonine (Thr172) within the catalytic subunit and activates AMPK in vitro [9Hong S.P. Leiper F.C. Woods A. Carling D. Carlson M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases.Proc. Natl. Acad. Sci. USA. 2003; 100: 8839-8843Crossref PubMed Scopus (451) Google Scholar]. Here, we have investigated whether LKB1 corresponds to the major AMPKK activity present in cell extracts. AMPKK purified from rat liver corresponds to LKB1, and blocking LKB1 activity in cells abolishes AMPK activation in response to different stimuli. These results identify a link between two protein kinases, previously thought to lie in unrelated, distinct pathways, that are associated with human diseases.