The LKB1 tumor suppressor negatively regulates mTOR signaling.
Germline mutations in LKB1, TSC2, or PTEN tumor suppressor genes result in hamartomatous syndromes with shared tumor biological features. The recent observations of LKB1-mediated activation of AMP-activated protein kinase (AMPK) and AMPK inhibition of mTOR through TSC2 prompted us to examine the biochemical and biological relationship between LKB1 and mTOR regulation. Here, we report that LKB1 is required for repression of mTOR under low ATP conditions in cultured cells in an AMPK- and TSC2-dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR. These findings position aberrant mTOR activation at the nexus of these germline neoplastic conditions and suggest the use of mTOR inhibitors in the treatment of Peutz-Jeghers syndrome.
Shaw
Reuben J
RJ
Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
Bardeesy
Nabeel
N
Manning
Brendan D
BD
Lopez
Lyle
L
Kosmatka
Monica
M
DePinho
Ronald A
RA
Cantley
Lewis C
LC
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003111:Colonic Polyps / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000473:pathology*; D016147:Genes, Tumor Suppressor; D006222:Hamartoma / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism*; D010580:Peutz-Jeghers Syndrome / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
D009097:Multienzyme Complexes; D012097:Repressor Proteins; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases