The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells

被引：375

作者：

She, QB

Solit, DB

Ye, Q

O'Reilly, KE

Lobo, J

Rosen, N ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA

来源：

CANCER CELL | 2005年 / 8卷 / 04期

关键词：

D O I：

10.1016/j.ccr.2005.09.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Tumor cells with mutated PTEN proliferate in an EGFR-independent manner. Induction of PTEN sensitizes cells to EGFR inhibition, and the combination causes synergistic apoptosis. Synergy is due to inhibition of two parallel pathways that phosphorylate the proapoptotic protein BAD at distinct sites. Serine 112 phosphorylation is EGFR/MEK/MAPK dependent, whereas serine 136 phosphorylation is PI3K/Akt dependent. Either phosphorylation is sufficient to sequester BAD to 143-3. BAD is released and apoptosis is induced only if both serines are dephosphorylated in response to inhibition of both pathways. Reduction of BAD expression by RNA interference prevents apoptosis in response to pathway inhibition. Thus, BAD integrates the antiapoptotic effects of both pathways. Combined inhibition of EGFR and PI3K signaling may be a useful therapeutic strategy.

引用

收藏

页码：287 / 297

页数：11

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