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

CHO cells expressing α₅β₁ integrin are more resistant to apoptosis and express more Bcl-2 than the same cells engineered to express α_vβ₁ or cytoplasmically truncated α₅Δcβ₁ integrin as their main fibronectin receptor. The Bcl-2 up-regulation by α₅β 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-κB and CREB transcription factors also enhance the integrin-dependent regulation of Bcl-2 expression in the α₅β₁ 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 α_vβ₁ and α₅Δcβ₁ cells. These cell lines differed from one another in two Bcl-2-regulating pathways: adhesion through α_vβ₁ failed to activate Akt, allowing forkhead to suppress Bcl-2 transcription, whereas α₅Δcβ ₁ did not activate NF-κB 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 α ₅β₁ integrin.