TY - JOUR
T1 - Migfilin interacts with Src and contributes to cell-matrix adhesion-mediated survival signaling
AU - Zhao, Jingping
AU - Zhang, Yongjun
AU - Ithychanda, Sujay Subbayya
AU - Tu, Yizeng
AU - Chen, Ka
AU - Qin, Jun
AU - Wu, Chuanyue
PY - 2009/12/4
Y1 - 2009/12/4
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.045021
DO - 10.1074/jbc.M109.045021
M3 - Article
C2 - 19833732
AN - SCOPUS:71749089459
SN - 0021-9258
VL - 284
SP - 34308
EP - 34320
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 49
ER -