Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis
Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis
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DOI：
10.1038/ncb1026
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发表时间：
2003-08-01
影响因子：
21.3
通讯作者：
Brugge, JS
中科院分区：
文献类型：
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作者：
Reginato, MJ;Mills, KR;Brugge, JS
上皮细胞必须依附于细胞外基质（ECM）才能存活，因为脱离基质会引发细胞凋亡或凋亡(1)。整合素是细胞与ECM蛋白之间粘附的主要介质，并传递细胞存活所需的信号(2)。最近的证据表明，整合素受体与生长因子受体偶联调节多种生物学功能(2)；然而，参与细胞存活协调调节的机制尚不清楚，负责anoikis的介质尚未被很好地表征。在这里，我们发现促凋亡蛋白Bim是上皮细胞凋亡的关键介质。细胞脱离后，Bim被强烈诱导，通过RNA干扰（RNA interference, RNAi）下调Bim的表达可抑制疾病的发生。脱离诱导的Bim表达需要缺乏β(1)-整合素参与、EGF受体（EGFR）表达下调和Erk信号传导抑制。过表达的EGFR与整合素调控分离，导致Erk的激活维持在悬浮状态，并阻断了Bim的表达和代谢。因此，Bim作为整合素和生长因子信号到Erk通路的关键传感器，这种协调调节的丧失可能导致肿瘤进展。
Epithelial cells must adhere to the extracellular matrix (ECM) for survival, as detachment from matrix triggers apoptosis or anoikis(1). Integrins are major mediators of adhesion between cells and ECM proteins, and transduce signals required for cell survival(2). Recent evidence suggests that integrin receptors are coupled to growth factor receptors in the regulation of multiple biological functions(2); however, mechanisms involved in coordinate regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we identify the pro-apoptotic protein Bim as a critical mediator of anoikis in epithelial cells. Bim is strongly induced after cell detachment and downregulation of Bim expression by RNA interference (RNAi) inhibits anoikis. Detachment-induced expression of Bim requires a lack of beta(1)-integrin engagement, downregulation of EGF receptor (EGFR) expression and inhibition of Erk signalling. Overexpressed EGFR was uncoupled from integrin regulation, resulting in the maintenance of Erk activation in suspension, and a block in Bim expression and anoikis. Thus, Bim functions as a key sensor of integrin and growth factor signals to the Erk pathway, and loss of such coordinate regulation may contribute to tumour progression.