Differential effects of the integrins alpha9beta1, alphavbeta3, and alphavbeta6 on cell proliferative responses to tenascin. Roles of the beta subunit extracellular and cytoplasmic domains.
Members of the integrin family manifest considerable overlap in ligand specificity, and many cells have the capacity to express multiple integrin receptors for the same ligand. For example, at least 5 different integrins recognize tenascin as a ligand, and 4 of these bind to the same region of the protein, the third fibronectin type III repeat (TNfn3). We utilized colon carcinoma cells (SW480) that do not normally attach to TNfn3 to examine the possibility that ligation of different integrin receptors for this ligand would induce different effects on cell behavior and intracellular signaling. Heterologous expression of the tenascin receptors alphavbeta3 and alpha9beta1 produced comparable effects on cell adhesion and spreading on TNfn3, but alphavbeta3-transfectants proliferated considerably better on each concentration examined. alphavbeta6-transfectants attached (although less avidly), but completely failed to spread or proliferate. Expression of a chimeric beta subunit composed of the beta3 extracellular domain fused to the beta6 transmembrane and cytoplasmic domains resulted in adhesion and spreading similar to that seen with beta3-transfectants, but considerably less proliferation. When the same cell lines were plated on fibronectin, alphavbeta6-transfectants spread and proliferated as well as cells transfected with the chimeric beta3/beta6 subunit, but, again, neither cell line proliferated as well as cells expressing alphavbeta3. Cell proliferation was always associated with spreading and with phosphorylation of the focal adhesion kinase, paxillin, and the mitogen-activated kinase, Erk2, but cell attachment in the absence of spreading or proliferation was not associated with phosphorylation of any of these proteins. These data suggest that different integrin receptors for a single ligand can produce markedly different effects on cell proliferation, and that both the extracellular and cytoplasmic domains of integrin beta subunits contribute to these differences.
Yokosaki
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Y
Lung Biology Center, Center for Occupational and Environmental Health, Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA.
Monis
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H
Chen
J
J
Sheppard
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D
D015703:Antigens, CD / Q000502:physiology; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000502:physiology; D002455:Cell Division; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005110:Extracellular Space; D005353:Fibronectins / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D039001:Integrin alpha Chains; D039564:Integrin alphaV; D039641:Integrin beta Chains; D019012:Integrin beta1 / Q000502:physiology; D039661:Integrin beta3; D016023:Integrins / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011946:Receptors, Antigen / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D019063:Tenascin / Q000502:physiology*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D039001:Integrin alpha Chains; D039564:Integrin alphaV; D039641:Integrin beta Chains; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D010980:Platelet Membrane Glycoproteins; D011946:Receptors, Antigen; D019063:Tenascin; C028641:Tn receptor; C084613:integrin alpha9; C072170:integrin beta6; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1