1. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis
- Author
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Ma, Li, Chen, Zhenbang, Erdjument-Bromage, Hediye, Tempst, Paul, and Pandolfi, Pier Paolo
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,MAP Kinase Signaling System ,Nude ,Molecular Sequence Data ,Amino Acid Sequence ,Animals ,Cell Line ,Extracellular Signal-Regulated MAP Kinases ,Humans ,Kidney ,Mice ,Neoplasm Transplantation ,Neoplasms ,Phosphorylation ,Protein Kinases ,Repressor Proteins ,Ribosomal Protein S6 Kinases ,70-kDa ,Serine ,Tuberous Sclerosis ,Tumor Suppressor Proteins ,Mice, Nude ,In Vitro Techniques ,Tuberous Sclerosis Complex 1 Protein ,Tuberous Sclerosis Complex 2 Protein ,neoplasms ,TOR Serine-Threonine Kinases ,Ribosomal Protein S6 Kinases, 70-kDa ,nervous system diseases - Abstract
SummaryTuberous 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.
- Published
- 2004