Differential role of beta(1C) and beta(1A) integrin cytoplasmic variants in modulating focal adhesion kinase, protein kinase B/AKT, and Ras/mitogen-activated protein kinase pathways

The integrin cytoplasmic domain modulates cell proliferation, adhesion, mig ration, and intracellular signaling. The beta(1) integrin subunits, beta(1C ) and beta(1A), that contain variant cytoplasmic domains differentially aff ect cell proliferation; beta(1C) inhibits proliferation, whereas beta(1A) p romotes it. We investigated the ability of beta(1C) and beta(1A) to modulat e integrin-mediated signaling events that affect cell proliferation and sur vival in Chinese hamster ovary stable cell lines expressing either human be ta(1C) or human beta(1A). The different cytodomains of either beta(1C) or b eta(1A) did not affect either association with the endogenous alpha(2), alp ha(V), and alpha(5) subunits or cell adhesion to fibronectin or TS2/16, a m Ab to human beta(1). Upon engagement of endogenous and exogenous integrins by fibronectin, cells expressing beta(1C) showed significantly inhibited ex tracellular signal-regulated kinase (ERK) 2 activation compared with beta(1 A) stable cell lines. In contrast, focal adhesion kinase phosphorylation an d Protein Kinase B/AKT activity were not affected. Selective engagement of the exogenously expressed beta(1C) by TS2/16 led to stimulation of Protein Kinase B/AKT phosphorylation but not of ERK2 activation; in contrast, beta( 1A) engagement induced activation of both proteins. We show that Pas activa tion was strongly reduced in beta(1C) stable cell lines in response to fibr onectin adhesion and that expression of constitutively active Ras, Ras 61 ( L), rescued beta(1C)-mediated down-regulation of ERK2 activation. Inhibitio n of cell proliferation in B-1C stable cell lines was attributable to an in hibitory effect of beta(1C) on the Ras/MAP kinase pathway because expressio n of activated MAPK kinase rescued beta(1C) antiproliferative effect. These findings show that the beta(1C) variant, by means of a unique signaling me chanism, selectively inhibits the MAP kinase pathway by preventing Ras acti vation without affecting either survival signals stimulated by integrins or cellular interactions with the extracellular matrix. These findings highli ght a role for beta(1)-specific cytodomain sequences in maintaining an intr acellular balance of proliferation and survival signals.