alpha5beta1 integrin stimulates Bcl-2 expression and cell survival through Akt, focal adhesion kinase, and Ca2+/calmodulin-dependent protein kinase IV.
CHO cells expressing alpha5beta1 integrin are more resistant to apoptosis and express more Bcl-2 than the same cells engineered to express alphavbeta1 or cytoplasmically truncated alpha5Deltacbeta1 integrin as their main fibronectin receptor. The Bcl-2 up-regulation by alpha5beta1 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-kappaB and CREB transcription factors also enhance the integrin-dependent regulation of Bcl-2 expression in the alpha5beta1cells. A forkhead transcription factor, which is inactivated by Akt, blocked Bcl-2 expression. The FAK pathway was found to be defective in both the alphavbeta1 and alpha5Deltacbeta1 cells. These cell lines differed from one another in two Bcl-2-regulating pathways: adhesion through alphavbeta1 failed to activate Akt, allowing forkhead to suppress Bcl-2 transcription, whereas alpha5Deltacbeta1 did not activate NF-kappaB 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 alpha5beta1 integrin.
Lee
Byung-Heon
BH
Department of Biochemistry and Research Institute for Cell & Matrix Biology, School of Medicine, Kyungpook National University, Daegu 700-422, Korea. leebh@mail.knu.ac.kr
Ruoslahti
Erkki
E
D000818:Animals; D016466:CHO Cells; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002470:Cell Survival; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; D039081:Integrin alpha5beta1; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases