Migfilin interacts with Src and contributes to cell-matrix adhesion-mediated survival signaling.
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.
Zhao
Jianping
J
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Zhang
Yongjun
Y
Ithychanda
Sujay Subbayya
SS
Tu
Yizeng
Y
Chen
Ka
K
Qin
Jun
J
Wu
Chuanyue
C
D023102:Anoikis; D017209:Apoptosis; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D034622:RNA Interference; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C473794:FBLIM1 protein, human; D005982:Glutathione Transferase; D019061:src-Family Kinases