The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells
The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells
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DOI：
10.1016/j.ccr.2005.09.006
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发表时间：
2005-10-01
期刊：
影响因子：
50.3
通讯作者：
Rosen, N
中科院分区：
文献类型：
--
作者：
She, QB;Solit, DB;Rosen, N
具有突变的PTEN的肿瘤细胞以EGFR非依赖性方式增殖。PTEN的诱导使细胞对EGFR抑制敏感，并且组合引起协同凋亡。协同作用是由于两个平行的途径，磷酸化的促凋亡蛋白BAD在不同的网站的抑制。丝氨酸112磷酸化是EGFR/MEK/MAPK依赖的，而丝氨酸136磷酸化是PI 3 K/Akt依赖的。任何一种磷酸化都足以将BAD螯合到143-3。只有当两种丝氨酸都被去磷酸化以响应两种途径的抑制时，BAD才被释放并诱导细胞凋亡。通过RNA干扰减少BAD表达防止响应于通路抑制的细胞凋亡。因此，BAD整合了两种途径的抗凋亡作用。EGFR和PI 3 K信号传导的联合抑制可能是有用的治疗策略。
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.