Integrin and FAK-mediated MAPK activation is required for cyclic strain mitogenic effects in Caco-2 cells

Rhythmic strain stimulates Caco-2 proliferation. We asked whether mitogen-a ctivated protein kinase (MAPK) activation mediates strain mitogenicity and characterized upstream signals regulating MAPK. Caco-2 cells were subjected to strain on collagen I-precoated membranes or antibodies to integrin subu nits. Twenty-four hours of cyclic strain increased cell numbers compared wi th static conditions. MAPK-extracellular signal-regulated kinase (ERK) kina se inhibition (20 muM PD-98059) blocked strain mitogenicity. p38 Inhibition (10 muM SB-202190) did not. Strain rapidly and time-dependently activated focal adhesion kinase (FAK), paxillin, ERK1 and 2, and p38 on collagen. c-J un NH2-terminal kinase (JNK) 1 and 2 exhibited delayed activation. Similar activation occurred when Caco-2 cells were subjected to strain on a substra te of functional antibody to the alpha2-, alpha3-, alpha6-, or beta1-integr in subunits but not on a substrate of functional antibody to the alpha5-sub unit. FAK inhibition by FAK397 transfection blocked ERK2 and JNK1 activatio n by in vitro kinase assays, but pharmacological protein kinase C inhibitio n did not block ERK1 or 2 activation by strain. Strain-induced ERK signals mediate strain's mitogenic effects and may require integrins and FAK activa tion.