Integrin α3, But Not β1, Regulates Islet Cell Survival and Function via PI3K/Akt Signaling Pathways

beta 1-Integrin is a well-established regulator of beta-cell activities; however, the role of its associated alpha-subunits is relatively unknown. Previously, we have shown that human fetal islet and INS-1 cells highly express alpha 3 beta 1-integrin and that collagens I and IV significantly enhance their survival and function; in addition, blocking beta 1 function in the fetal islet cells decreased adhesion on collagen I and increased apoptosis. The present study investigates the effect of blocking alpha 3. Using alpha 3 blocking antibody or small interfering RNA, the effects of alpha 3-integrin blockade were examined in isolated human fetal or adult islet cells or INS-1 cells, cultured on collagens I or IV. In parallel, beta 1 blockade was analyzed in INS-1 cells. Perturbing alpha 3 function in human islet or INS-1 cells resulted in significant decreases in cell function (adhesion, spreading, proliferation and Pdx1 and insulin expression/secretion), primarily on collagen IV. A significant decrease in focal adhesion kinase and ERK1/2 phosphorylation and increased caspase3 cleavage were observed on both collagens. These effects were similar to changes after beta 1 blockade. Interestingly, only alpha 3 blockade reduced expression of phospho-Akt and members of its downstream signaling cascades (glycogen synthase kinase beta and X-linked inhibitor of apoptosis), demonstrating a specific effect of alpha 3 on the phosphatidylinositol 3-kinase/Akt pathway. These results suggest that alpha 3- as well as beta 1-integrin-extracellular matrix interactions are critical for modulating beta-cell survival and function through specialized signaling cascades and enhance our understanding of how to improve islet microenvironments for cell-based treatments of diabetes. (Endocrinology 152: 424-435, 2011)