Giannoni E, Buricchi F, Grimaldi G, Parri M, Cialdai F, Taddei M L, Raugei G, Ramponi G, Chiarugi P
Department of Biochemical Sciences, University of Florence, Florence, Italy.
Cell Death Differ. 2008 May;15(5):867-78. doi: 10.1038/cdd.2008.3. Epub 2008 Feb 8.
Proper attachment to the extracellular matrix (ECM) is essential for cell survival. The loss of integrin-mediated cell-ECM contact results in an apoptotic process termed anoikis. However, mechanisms involved in regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we demonstrate that reactive oxygen species (ROS) produced through the involvement of the small GTPase Rac-1 upon integrin engagement exert a mandatory role in transducing a pro-survival signal that ensures that cells escape from anoikis. In particular, we show that ROS are responsible for the redox-mediated activation of Src that trans-phosphorylates epidermal growth factor receptor (EGFR) in a ligand-independent manner. The redox-dependent phosphorylation of EGFR activates both extracellular signal-regulated protein kinase and Akt downstream signalling pathways, culminating in degradation of the pro-apoptotic protein Bim. Hence, our results shed new light on the mechanism granting the adhesion-dependent antiapoptotic effect, highlighting a fundamental role of ROS-mediated Src regulation in ensuring anoikis protection.
与细胞外基质（ECM）的正确附着对于细胞存活至关重要。整合素介导的细胞与ECM接触的丧失会导致一种称为失巢凋亡的凋亡过程。然而，细胞存活调控所涉及的机制仍知之甚少，负责失巢凋亡的介质也尚未得到充分表征。在此，我们证明，整合素参与后通过小GTP酶Rac-1产生的活性氧（ROS）在转导确保细胞逃脱失巢凋亡的促存活信号中发挥着强制性作用。特别是，我们表明ROS负责Src的氧化还原介导的激活，Src以不依赖配体的方式对表皮生长因子受体（EGFR）进行反式磷酸化。EGFR的氧化还原依赖性磷酸化激活细胞外信号调节蛋白激酶和Akt下游信号通路，最终导致促凋亡蛋白Bim的降解。因此，我们的结果为赋予黏附依赖性抗凋亡作用的机制提供了新的线索，突出了ROS介导的Src调节在确保失巢凋亡保护中的基本作用。
