LKB1; linking cell structure and tumor suppression

Abstract

Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

Phosphorylation of Serine 399 in LKB1 Protein Short Form by Protein Kinase Cζ Is Required for Its Nucleocytoplasmic Transport and Consequent AMP-activated Protein Kinase (AMPK) Activation

“…Liver kinase B1 (LKB1) is a tumor suppressor gene whose inactivating mutations are implicated in various sporadic cancers and are responsible for the majority of Peutz-Jeghers syndrome cases (1)(2)(3)(4)(5). Expression of LKB1 is ubiquitous in many cell types and tissues, and its high expression in fetal tissues is consistent with the critical role of LKB1 in embryonic development (6 -9).…”

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

“…Although AMPK, Sik2 and Mark2 have been proposed as major proximate regulators for Crtc2 (Lizcano et al, 2004;Dentin et al, 2007;Fu and Screaton, 2008;Hezel and Bardeesy, 2008), Sik1 has also been suggested as an important kinase inhibitor for Crtc1 transcriptional activity (Katoh et al, 2006). Further, SIK1 is a Crtc1/ cAMP/CREB target gene whose induction is proposed to phosphorylate and mediate a negative feedback loop on Crtc1 in neuronal cells .…”

The epithelial polarity program: machineries involved and their hijacking by cancer

“…Par4 is an established tumor suppressor, a substrate of aPKC and a master kinase, which phosphorylates Par1 and AMP activated protein kinase (AMPK/PKA), involved in a parallel polarity pathway important under conditions of energetic stress (Lee et al, 2007;Mirouse et al, 2007) (see Hezel and Bardeesy, 2008). Activation of Par4 promotes the polarization of intestinal epithelial cells in the absence of cell-cell contacts (Baas et al, 2004a).…”

“…Mutations in the tumor suppressor Par4 (LKB1), a kinase for AMPK, and a major inducer of cell polarity when activated, lead to the hereditable Peutz-Jeghers cancer syndrome, characterized by predisposition to a variety of rare intestinal cancer and other types of cancer (Wodarz and Nathke, 2007) (see Hezel and Bardeesy, 2008). The lipid phosphatase PTEN is also considered a tumor suppressor and controls the recruitment of the Par complex to the apical PM either directly or through the generation of PIP2 (MartinBelmonte et al, 2007).…”