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.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Line, Extracellular Signal-Regulated MAP Kinases, Humans, Kidney, MAP Kinase Signaling System, Mice, Mice, Nude, Molecular Sequence Data, Neoplasm Transplantation, Neoplasms, Phosphorylation, Protein Kinases, Repressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Serine, Tuberous Sclerosis, Tumor Suppressor Proteins
Amino Acid Sequence, Animals, Cell Line, Extracellular Signal-Regulated MAP Kinases, Humans, Kidney, MAP Kinase Signaling System, Mice, Mice, Nude, Molecular Sequence Data, Neoplasm Transplantation, Neoplasms, Phosphorylation, Protein Kinases, Repressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Serine, Tuberous Sclerosis, Tumor Suppressor Proteins
Cell
Date: Apr. 22, 2005
PubMed ID: 15851026
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