Zhao Jianping, Zhang Yongjun, Ithychanda Sujay Subbayya, Tu Yizeng, Chen Ka, Qin Jun, Wu Chuanyue
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
J Biol Chem. 2009 Dec 4;284(49):34308-20. doi: 10.1074/jbc.M109.045021. Epub 2009 Oct 15.
Integrin-mediated cell-extracellular matrix (ECM) adhesion is essential for protection of epithelial cells against apoptosis, but the underlying mechanism is incompletely understood. Here we show that migfilin, an integrin-proximal adaptor protein, interacts with Src and contributes to cell-ECM-mediated survival signaling. Loss of cell-ECM adhesion markedly reduces the migfilin level in untransformed epithelial cells and concomitantly induces apoptosis. Overexpression of migfilin substantially desensitizes cell detachment-induced apoptosis. Conversely, depletion of migfilin promotes apoptosis despite the presence of cell-ECM adhesion. At the molecular level migfilin directly interacts with Src, and the migfilin binding surface overlaps with the inhibitory intramolecular interaction sites in Src. Consequently, the binding of migfilin activates Src, resulting in suppression of apoptosis. Our results reveal a novel mechanism by which cell-ECM adhesion regulates Src activation and survival signaling. This migfilin-mediated signaling pathway is dysfunctional in multiple types of carcinoma cells, which likely contributes to aberrant Src activation and anoikis resistance in the cancerous cells.
整合素介导的细胞-细胞外基质（ECM）黏附对于保护上皮细胞免于凋亡至关重要，但其潜在机制尚未完全阐明。在此我们表明，migfilin，一种整合素近端衔接蛋白，与Src相互作用并有助于细胞-ECM介导的存活信号传导。细胞-ECM黏附的丧失显著降低未转化上皮细胞中的migfilin水平，并随之诱导凋亡。Migfilin的过表达显著降低细胞脱离诱导的凋亡敏感性。相反，尽管存在细胞-ECM黏附，migfilin的缺失仍促进凋亡。在分子水平上，migfilin直接与Src相互作用，且migfilin结合表面与Src中的抑制性分子内相互作用位点重叠。因此，migfilin的结合激活Src，从而抑制凋亡。我们的结果揭示了一种细胞-ECM黏附调节Src激活和存活信号传导的新机制。这种migfilin介导的信号通路在多种类型的癌细胞中功能失调，这可能导致癌细胞中Src的异常激活和失巢凋亡抗性。
