title: Integrin {alpha}3, but not {beta}1, regulates islet cell survival and function via PI3K/Akt signaling pathways.
abstract: β1-integrin is a well-established regulator of β-cell activities; however, the role of its associated α-subunits is relatively unknown. Previously, we have shown that human fetal islet and INS-1 cells highly express α3β1-integrin and that collagens I and IV significantly enhance their survival and function; in addition, blocking β1 function in the fetal islet cells decreased adhesion on collagen I and increased apoptosis. The present study investigates the effect of blocking α3. Using α3 blocking antibody or small interfering RNA, the effects of α3-integrin blockade were examined in isolated human fetal or adult islet cells or INS-1 cells, cultured on collagens I or IV. In parallel, β1 blockade was analyzed in INS-1 cells. Perturbing α3 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 β1 blockade. Interestingly, only α3 blockade reduced expression of phospho-Akt and members of its downstream signaling cascades (glycogen synthase kinase β and X-linked inhibitor of apoptosis), demonstrating a specific effect of α3 on the phosphatidylinositol 3-kinase/Akt pathway. These results suggest that α3- as well as β1-integrin-extracellular matrix interactions are critical for modulating β-cell survival and function through specialized signaling cascades and enhance our understanding of how to improve islet microenvironments for cell-based treatments of diabetes.
authors.affiliation: Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, Ontario N6C 2V5, Canada.
authors.forename: Mansa
authors.initials: M
authors.lastname: Krishnamurthy
authors.forename: Jinming
authors.initials: J
authors.lastname: Li
authors.forename: George F
authors.initials: GF
authors.lastname: Fellows
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rosenberg
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Goodyer
authors.forename: Rennian
authors.initials: R
authors.lastname: Wang
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D039422:Integrin alpha3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000906:Antibodies; D002070:Butadienes; D039422:Integrin alpha3; D019012:Integrin beta1; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C113580:U 0126; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin