α 5 β 1 integrin stimulates Bcl‐2 expression and cell survival through Akt, focal adhesion kinase, and Ca 2+ /calmodulin‐dependent protein kinase IV

CHO cells expressing α 5 β 1 integrin are more resistant to apoptosis and express more Bcl‐2 than the same cells engineered to express α v β 1 or cytoplasmically truncated α 5 Δcβ 1 integrin as their main fibronectin receptor. The Bcl‐2 up‐regulation by α 5 β 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 Ca 2+ /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 α 5 β 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 α v β 1 and α 5 Δcβ 1 cells. These cell lines differed from one another in two Bcl‐2‐regulating pathways: adhesion through α v β 1 failed to activate Akt, allowing forkhead to suppress Bcl‐2 transcription, whereas α 5 Δcβ 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 5 β 1 integrin. © 2005 Wiley‐Liss, Inc.