α5β1 integrin stimulates Bcl-2 expression and cell survival through Akt, focal adhesion kinase, and Ca2+/calmodulin-dependent protein kinase IV

CHO cells expressing alpha(5)beta(1) integrin are more resistant to apoptosis and express more Bcl-2 than the same cells engineered to express alpha(5)beta(1) or cytoplasmically truncated alpha(5)Delta c beta(1) integrin as their main fibronectin receptor. The Bcl-2 up-regulation by alpha(5)beta(1) is mediated, at least in part, by the focal adhesion kinase (FAK) and phosphatidylinositol-3 kinase (PI3K)/Akt pathways. Here, we show that integrin-mediated activation of Ca2+/calmodulin-dependent protein kinase (CaMK) IV, and the NF-kappa B and CREB transcription factors also enhance the integrin-dependent regulation of Bcl-2 expression in the alpha(5)beta(1) cells. A forkhead transcription factor, which is inactivated by Akt, blocked Bcl-2 expression. The FAK pathway was found to be defective in both the alpha(v)beta(1) and alpha(5)Delta c beta(1) cells. These cell lines differed from one another in two Bcl-2-regulating pathways: adhesion through alpha(v)beta(1) failed to activate Akt, allowing forkhead to suppress Bcl-2 transcription, whereas alpha(5)Delta c beta(1) did not activate NF-kappa B and CREB, presumably because CaMK IV was not activated. Our results indicate that three pathways, the FAK, PI3K/Akt, and CaMK IV mediate the survival-supporting activity of alpha(5)beta(1) integrin.