Phosphorylation and functional inactivation of TSC2 by Erk: Implications for tuberous sclerosis and cancer pathogenesis Journal Article


Authors: Ma, L.; Chen, Z. B.; Erdjument-Bromage, H.; Tempst, P.; Pandolfi, P. P.
Article Title: Phosphorylation and functional inactivation of TSC2 by Erk: Implications for tuberous sclerosis and cancer pathogenesis
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.
Keywords: in-vivo; 3-kinase/akt pathway; cell-growth; map kinase; signaling pathway; gene-products; initiation-factor 4e; translational control; tumor-suppressor proteins; p70 s6 kinase
Journal Title: Cell
Volume: 121
Issue: 2
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2005-04-22
Start Page: 179
End Page: 193
Language: English
ACCESSION: WOS:000242021900007
DOI: 10.1016/j.cell.2005.02.031
PROVIDER: wos
PUBMED: 15851026
Notes: --- - Article - S - "Source: Wos"
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  1. Zhenbang Chen
    13 Chen
  2. Paul J Tempst
    324 Tempst
  3. Li Ma
    6 Ma