Reginato Mauricio J, Mills Kenna R, Paulus Jessica K, Lynch Danielle K, Sgroi Dennis C, Debnath Jayanta, Muthuswamy Senthil K, Brugge Joan S
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Nat Cell Biol. 2003 Aug;5(8):733-40. doi: 10.1038/ncb1026.
Epithelial cells must adhere to the extracellular matrix (ECM) for survival, as detachment from matrix triggers apoptosis or anoikis. Integrins are major mediators of adhesion between cells and ECM proteins, and transduce signals required for cell survival. Recent evidence suggests that integrin receptors are coupled to growth factor receptors in the regulation of multiple biological functions; 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.
上皮细胞必须附着于细胞外基质（ECM）才能存活，因为与基质脱离会触发细胞凋亡或失巢凋亡。整合素是细胞与ECM蛋白之间黏附的主要介质，并传导细胞存活所需的信号。最近的证据表明，在多种生物学功能的调节中，整合素受体与生长因子受体相互偶联；然而，细胞存活的协同调节机制仍知之甚少，且负责失巢凋亡的介质尚未得到充分表征。在此，我们确定促凋亡蛋白Bim是上皮细胞失巢凋亡的关键介质。细胞脱离后Bim被强烈诱导，通过RNA干扰（RNAi）下调Bim表达可抑制失巢凋亡。Bim的脱离诱导表达需要缺乏β1整合素结合、表皮生长因子受体（EGFR）表达下调以及Erk信号传导的抑制。过表达的EGFR与整合素调节解偶联，导致悬浮状态下Erk激活得以维持，并阻断Bim表达和失巢凋亡。因此，Bim作为整合素和生长因子信号至Erk途径的关键传感器，这种协同调节的丧失可能促进肿瘤进展。
