Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Humans
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In Vitro Techniques
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Kidney / cytology
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MAP Kinase Signaling System / physiology
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Mice
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Mice, Nude
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Molecular Sequence Data
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Neoplasm Transplantation
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Neoplasms / etiology*
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Neoplasms / metabolism*
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Phosphorylation
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Protein Kinases / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Serine / metabolism
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TOR Serine-Threonine Kinases
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Tuberous Sclerosis / etiology*
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Tuberous Sclerosis / metabolism*
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Repressor Proteins
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TSC1 protein, human
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TSC2 protein, human
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Tsc1 protein, mouse
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Serine
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 2
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Extracellular Signal-Regulated MAP Kinases