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

Abstract	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.
Authors	Michael N Corradetti, Ken Inoki, Nabeel Bardeesy, Ronald A DePinho, Kun-Liang Guan
Journal	Genes & development (Genes Dev) Vol. 18 Issue 13 Pg. 1533-8 (Jul 01 2004) ISSN: 0890-9369 [Print] United States
PMID	15231735 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Adaptor Proteins, Signal Transducing Carrier Proteins Cell Cycle Proteins EIF4EBP1 protein, human Eif4ebp1 protein, mouse Eukaryotic Initiation Factors Multienzyme Complexes Phosphoproteins Repressor Proteins TSC2 protein, human Tsc2 protein, mouse Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Deoxyglucose Protein Kinases MTOR protein, human mTOR protein, mouse Protein Serine-Threonine Kinases Ribosomal Protein S6 Kinases STK11 protein, human Stk11 protein, mouse TOR Serine-Threonine Kinases AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases
Topics	AMP-Activated Protein Kinase Kinases AMP-Activated Protein Kinases Adaptor Proteins, Signal Transducing Animals Carrier Proteins (metabolism) Cell Cycle Proteins Cells, Cultured Deoxyglucose (pharmacology) Eukaryotic Initiation Factors Fibroblasts Genes, Tumor Suppressor HeLa Cells (drug effects) Humans Mice Multienzyme Complexes (metabolism) Mutation Peutz-Jeghers Syndrome (genetics, metabolism) Phosphoproteins (metabolism) Phosphorylation Protein Kinases (metabolism) Protein Serine-Threonine Kinases (genetics, metabolism) RNA Interference Repressor Proteins (genetics, metabolism) Ribosomal Protein S6 Kinases (metabolism) Signal Transduction TOR Serine-Threonine Kinases Tuberous Sclerosis (genetics, metabolism) Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins

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