Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation

被引:179
作者
Okano, J
Gaslightwala, I
Birnbaum, MJ
Rustgi, AK
Nakagawa, H
机构
[1] Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA
[2] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA
[3] Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA
[4] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M004112200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Overexpression of epidermal growth factor receptor (EGFR) in certain cancers is well established. There is growing evidence that epidermal growth factor (EGF) activates Akt/protein kinase B (PKB) in a phosphoinositide 3-OH kinase (PI3K)-dependent manner, but it is not yet clear which Akt isoforms are involved in this signal transduction pathway. We investigated the functional regulation of three Akt isoforms, Akt1/PKB alpha, Akt2/PKB beta, and Akt3/PKB gamma, in esophageal cancer cells where EGFR is frequently overexpressed. Upon EGF simulation, phosphorylation of Akt1 at the Ser-473 residue was remarkably induced. This result was corroborated by in vitro Akt kinase assays using glycogen synthase kinase 3 beta as the substrate. PI3K inhibitors, wortmannin or LY294002, significantly blocked the Akt kinase activity induced by EGF. Akt2 activity was evaluated by electrophoretic mobility shift assays. Robust activation of Akt2 by EGF was observed in some cell lines in a PI3K-dependent manner. EGF-induced Akt3 activation was demonstrated by Ser-472 phosphorylation of Akt3 but in a restrictive fashion. In aggregate, EGF-mediated activation of Akt isoforms is overlapping and distinctive. The mechanism by which EGFR recruits the PI3K/Akt pathway was in part differentially regulated at the level of Ras but independent of heterodimerization of EGFR with either ErbB2 or ErbB3 based upon functional dissection of pathways in esophageal cancer cell lines.
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页码:30934 / 30942
页数:9
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