Integrin {alpha}3, but not {beta}1, regulates islet cell survival and function via PI3K/Akt signaling pathways

Endocrinology. 2011 Feb;152(2):424-35. doi: 10.1210/en.2010-0877. Epub 2010 Dec 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Androstadienes / pharmacology
  • Animals
  • Antibodies / pharmacology
  • Blotting, Western
  • Butadienes / pharmacology
  • Cell Line
  • Fluorescent Antibody Technique
  • Humans
  • In Vitro Techniques
  • Integrin alpha3 / genetics
  • Integrin alpha3 / immunology
  • Integrin alpha3 / metabolism*
  • Integrin beta1 / genetics
  • Integrin beta1 / immunology
  • Integrin beta1 / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism*
  • Middle Aged
  • Nitriles / pharmacology
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Wortmannin


  • Androstadienes
  • Antibodies
  • Butadienes
  • Integrin alpha3
  • Integrin beta1
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • U 0126
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Wortmannin