Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway.
Integrin signaling plays a critical role in many aspects of normal growth, differentiation, and injury response. In the adult, alpha8beta1 is expressed in alveolar myofibroblasts and is upregulated in pulmonary fibrosis and other models of organ injury. Following injury, survival of fibronectin-producing myofibroblasts cells is an important determinant of development of fibrosis. Using stable alpha8-transfected cell lines, we show that interactions of alpha8beta1 with its ligand, fibronectin, promote cell survival during serum deprivation. Multiple cell signaling pathways were activated following fibronectin adhesion, including PI3 kinase and MAP kinase. However, the alpha8-mediated cell survival was blocked by LY294002, a PI3 kinase inhibitor, but not by staurosporine, a PKC inhibitor, or PD98059, a MAPK kinase inhibitor. A dominant negative construct of PI3 kinase also inhibited alpha8-mediated cell survival. Therefore, alpha8-mediated survival appears to be mediated by the PI3 kinase pathway. Survival of alpha8-expressing myofibroblasts may contribute to persistent fibrosis following injury.
Farias
Eduardo
E
Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Lu
Min
M
Li
Xianwu
X
Schnapp
Lynn M
LM
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D047468:Immunoprecipitation; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
D002867:Chromones; D004791:Enzyme Inhibitors; D005353:Fibronectins; D005419:Flavonoids; D016023:Integrins; D008024:Ligands; D009025:Morpholines; C094866:integrin alpha8beta1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D019311:Staurosporine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one