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 int egrin 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 (TNf n3). We utilized colon carcinoma cells (SW480) that do not normally at tach to TNfn3 to examine the possibility that ligation of different in tegrin receptors for this ligand would induce different effects on cel l behavior and intracellular signaling. Heterologous expression of the tenascin receptors alpha v beta 3 and alpha 9 beta 1 produced compara ble 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 chi meric beta subunit composed of the beta 3 extracellular domain fused t o the beta 6 transmembrane and cytoplasmic domains resulted in adhesio n and spreading similar to that seen with beta 3-transfectants, but co nsiderably 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 al pha v beta 3. Cell proliferation was always associated with spreading and with phosphorylation of the focal adhesion kinase, paxillin, and t he 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 r eceptors 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.