Editors' ChoiceCell Adhesion

Shifting from Spreading to Retraction

Science's STKE  13 Nov 2007:
Vol. 2007, Issue 412, pp. tw409
DOI: 10.1126/stke.4122007tw409

Integrin signaling has been implicated in both cell spreading (mediated through the small GTP-binding proteins Rac and cdc42) and cell retraction (mediated through RhoA). However, the mechanism whereby integrin temporally regulates these opposing processes--which must be coordinated in cell migration and wound repair--has been unclear. Noting that calpain cleavage of the cytoplasmic domain of integrin β3 is inhibited by tyrosine phosphorylation at Y759, Flevaris et al. expressed a phosphorylation-mimicking integrin β3 mutant in Chinese hamster ovary (CHO) cells, along with the wild-type integrin αIIb subunit, to investigate the role of calpain cleavage in integrin signaling. After determining that this R760E mutant was in fact resistant to calpain cleavage when expressed in CHO cells adherent to fibrinogen, the authors showed that cell-mediated clot retraction was inhibited with the R760E mutant cells, whereas cell spreading on fibrinogen was enhanced. In contrast, a deletion mutant that mimicked calpain cleavage exhibited defective cell spreading. RhoA was activated in cells with cleaved integrin β3, and pharmacological analysis indicated that defective spreading in the deletion mutant depended on activation of RhoA and Rho-dependent kinase (ROCK)-mediated retraction. A combination of pharmacological analysis and investigation of a dominant-negative c-Src mutant revealed that integrin β3-dependent c-Src signaling inhibited RhoA activation, thereby promoting cell spreading; integrin β3 cleavage disrupted its binding to c-Src, thereby relieving its inhibition of RhoA and stimulating retraction. Thus, the authors propose that the phosphorylation-regulated cleavage of the integrin β3 cytoplasmic domain by calpain switches the integrin β3 signal to promote retraction instead of spreading.

P. Flevaris, A. Stojanovic, H. Gong, A. Chishti, E. Welch, X. Du, A molecular switch that controls cell spreading and retraction. J. Cell Biol. 179, 553-565 (2007). [Abstract] [Full Text]