Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase-mediated mTOR activation in tuberous sclerosis and human cancer Journal Article

  

Authors:	Ma, L.; Teruya-Feldstein, J.; Bonner, P.; Bernardi, R.; Franz, D. N.; Witte, D.; Cordon-Cardo, C.; Pandolfi, P. P.
Article Title:	Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase-mediated mTOR activation in tuberous sclerosis and human cancer
Abstract:	Constitutive activation of extracellular signal-regulated kinases (Erk1/2) is frequently implicated in human cancers. Recently, aberrantly activated Erk was also found in brain lesions associated with tuberous sclerosis (TSC). We reported previously that Erk might contribute to tumorigenesis by phosphorylating TSC2 at specific residues, particularly S664. In our present study, 25 TSC-related cortical tubers or subependymal giant cell astrocytomas, as well as tissue microarrays of six types of human cancers, were analyzed for the expression of phospho-Erk (pErk) 1/2, S664-phospho-TSC2 (pTSC2), and phospho-S6 (pS6) by immunohistochemistry. We found that Erk-mediated TSC2 phosphorylation occurred at a high incidence and positively correlated with mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) activation in TSC-associated brain lesions as well as in various cancers. Interestingly, in certain types of cancers (e.g., breast carcinoma and colon carcinoma), S664-pTSC2 seemed to be a more sensitive marker than pErk. Furthermore, most of the pTSC2-positive samples (∼75%) were positive for pS6, but only 40% to 55% of the pS6-positive tumors exhibited TSC2 phosphorylation. Our results show that S664 TSC2 phosphorylation is a marker for Erk-mediated (as opposed to Akt-mediated) mTOR activation in TSC and human cancer. On the basis of these findings, TSC2 phosphorylation at S664 can be used to identify patients that may benefit from antitumor therapy with MAPK and mTOR inhibitors. Importantly, our results indicate that Erk-mediated phosphorylation and inactivation of TSC2 can be critical in development of hamartomatous lesions in TSC and cancer pathogenesis. ©2007 American Association for Cancer Research.
Keywords:	immunohistochemistry; mitogen activated protein kinase; protein kinase b; human tissue; protein expression; protein phosphorylation; human cell; pathogenesis; neoplasms; cells, cultured; map kinase signaling system; protein kinases; serine; embryo; incidence; subventricular zone; enzyme activation; transfection; phosphorylation; carcinogenesis; correlation analysis; kidney; breast carcinoma; mammalian target of rapamycin; tuberin; tumor suppressor proteins; immunoprecipitation; immunoblotting; extracellular signal-regulated map kinases; tissue array analysis; tissue microarray; colon carcinoma; giant cell; tuberous sclerosis; brain damage; protein s6; astrocytoma cell; ependyma cell
Journal Title:	Cancer Research
Volume:	67
Issue:	15
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2007-08-01
Start Page:	7106
End Page:	7112
Language:	English
DOI:	10.1158/0008-5472.can-06-4798
PUBMED:	17671177
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-34547645033&partnerID=40&md5=75a21b03bddf868181d9cab1e397dbc9
Notes:	--- - "Cited By (since 1996): 40" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/17775