Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis.
Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2 genes. TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH). Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. Importantly, expression of an Erk nonphosphorylatable TSC2 mutant in TSC2+/- tumor cells where Erk is constitutively activated blocks tumorigenecity in vivo, while wild-type TSC2 is ineffective. Our findings position the Ras/MAPK pathway upstream of the TSC complex and suggest that Erk may modulate mTOR signaling and contribute to disease progression through phosphorylation and inactivation of TSC2.
Ma
Li
L
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Chen
Zhenbang
Z
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Pandolfi
Pier Paolo
PP
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000209:etiology* / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D012694:Serine; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D048049:Extracellular Signal-Regulated MAP Kinases