Differential effects of the integrins alpha 9 beta 1, alpha v beta 3, and alpha v beta 6 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 alpha v beta 3 and alpha 9 beta 1 produced comparable effects on cell adhesion and spreading on TNfn3, but alpha v beta 3-transfectants proliferated considerably better on each concentration examined, alpha v beta 6-transfectants attached (although less avidly), but completely failed to spread or proliferate. Expression of a chimeric beta subunit composed of the beta 3 extracellular domain fused to the beta 6 transmembrane and cytoplasmic domains resulted in adhesion and spreading similar to that seen with beta 3-transfectants, but considerably less proliferation. When the same cell lines were plated on fibronectin, alpha v beta 6-transfectants spread and proliferated as well as cells transfected with the chimeric beta 3/beta 6 subunit, but, again, neither cell line proliferated as well as cells expressing alpha v beta 3. 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 cyto plasmic domains of integrin beta subunits contribute to these differences.