Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome.

By M. Corradetti, K. Inoki, N. Bardeesy, R. DePinho, K. Guan. Genes & Development, 2004

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Tuberous sclerosis complex (TSC) and Peutz-Jeghers syndrome (PJS) are dominantly inherited benign tumor syndromes that share striking histopathological similarities. Here we show that LKB1, the gene mutated in PJS, acts as a tumor suppressor by activating TSC2, the gene mutated in TSC. Like TSC2, LKB1 inhibits the phosphorylation of the key translational regulators S6K and 4EBP1. Furthermore, we show that LKB1 activates TSC2 through the AMP-dependent protein kinase (AMPK), indicating that LKB1 plays a role in cell growth regulation in response to cellular energy levels. Our results suggest that PJS and other benign tumor syndromes could be caused by dysregulation of the TSC2/mTOR pathway.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/48ef6c623ba78b260bfb87ee4d72b19e435b7e94

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Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. (2008, background): “In addition to inhibitory phosphorylation, TSC2 is activated by phosphorylation through the LKB1/AMPK pathway, which contributes to mTORC1 inhibition in the setting of energy deprivation and long-term hypoxic stress (Corradetti et al. 2004; Shaw et al. 2004; Liu et al. 2006).”
Defining the role of mTOR in cancer. (2007, background): “Like tsc1 and tsc2, the tumor suppressor genes linked to these diseases (pten, lkb1, nf1, and flcn respectively) encode proteins that restrict mTORC1 signaling (Baba et al., 2006; Corradetti et al., 2004; Eng, 2003; Johannessen et al., 2005; Shaw et al., 2004).”
Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 (2007, background): “Hyperactivation of mTOR caused by abrogation of its negative regulators (such as phosphatase and tension homolog (PTEN) and TSC2) has been identified in a number of human cancers, including prostate cancers, multiple myeloma and several hamartoma syndromes (including TSC, Cowden's disease and Peutz-”
Growing roles for the mTOR pathway. (2005, background): “Under conditions of energy deprivation that increase the AMP/ATP ratio, AMPK becomes active and phosphorylates TSC2 to stimulate its GAP activity [57], inhibiting rheb and presumably raptor–mTOR.”
Peutz–Jeghers syndrome: a systematic review and recommendations for management (2010, unknown): “It is an upstream regulator of AMP activated protein kinase (AMPK), thereby regulating the TSC pathway and acting as a negative regulator of the mammalian target of rapamycin (mTOR) pathway.(31) The mTOR pathway is particularly important as it is a final common pathway that is also dysregulated by o”
TOR signaling in growth and metabolism. (2006, background): “Indeed, LKB1 mutant cells exhibit hyperactive mTORC1 signaling (Corradetti et al., 2004; Shaw et al., 2004).”
Genetics and biology of pancreatic ductal adenocarcinoma. (2006, background): “…such as cell polarity and metabolism, and has been linked to specific signaling pathways including mTOR, the latter via its capacity to regulate AMPK (Bardeesy et al. 2002b; Ossipova et al. 2003; Baas et al. 2004; Corradetti et al. 2004; Lizcano et al. 2004; Shaw et al. 2004a,b, 2005; Hardie 2005).”
TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. (2006, background): “RNAi (Axin1, Axin2, and GFP as control) (Corradetti et al., 2004).”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “AMPK directly phosphorylates TSC2, which through an unknown mechanism leads to its activation and thus to the suppression of mTORC1 (Corradetti et al., 2004; Inoki et al., 2003b; Shaw et al., 2004) and is vital for cell survival under glucose deprivation conditions (Inoki et al., 2003b).”
AMPK phosphorylation of raptor mediates a metabolic checkpoint. (2008, background): “Upon LKB1- and AMP-dependent activation of AMPK by nutrient loss, AMPK directly phosphorylates the TSC2 tumor suppressor on conserved serine sites distinct from those targeted by other kinases, which constitutes one mechanism through which glucose and oxygen control mTORC1 activation (Inoki et al., ”
Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. (2009, background): “Under low-energy and other stress conditions, AMPK phosphorylates a number of targets to inhibit cellular growth and proliferation, including components of the growth-promoting mammalian target of rapamycin pathway.(38-40) Whether the apparent antitumor effect of metformin in our diabetic patients m”
AMPK in Health and Disease. (2009, methodology): “The mammalian AMPK domain limits were established experimentally by partial proteolysis (395), and a stable rat 1(68-163) fragment was expressed and crystallized in the presence of -cyclodextrin (an 1-4 linked heptaglucan), as had previously been performed for other starch binding domain structural ”