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"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/29946