Opposing roles of integrin alpha6Abeta1 and dystroglycan in laminin-mediated extracellular signal-regulated kinase activation.

Laminin–integrin interactions can in some settings activate the extracellular signal-regulated kinases (ERKs) but the control mechanisms are poorly understood. Herein, we studied ERK activation in response to two laminins isoforms (-1 and -10/11) in two epithelial cell lines. Both cell lines expressed {beta}1-containing integrins and dystroglycan but lacked integrin {alpha}6{beta}4. Antibody perturbation assays showed that both cell lines bound to laminin-10/11 via the {alpha}3{beta}1and {alpha}6{beta}1 integrins. Although laminin-10/11 was a stronger adhesion complex than laminin-1 for both cell lines, both laminins activated ERK in only one of the two cell lines. The ERK activation was mediated by integrin {alpha}6{beta}1 and not by {alpha}3{beta}1 or dystroglycan. Instead, we found that dystroglycan-binding domains of both laminin-1 and -10/11 suppressed integrin {alpha}6{beta}1-mediated ERK activation. Moreover, the responding cell line expressed the two integrin {alpha}6 splice variants, {alpha}6A and {alpha}6B, whereas the nonresponding cell line expressed only {alpha}6B. Furthermore, ERK activation was seen in cells transfected with the integrin {alpha}6A subunit, but not in {alpha}6B-transfected cells. We conclude that laminin-1 and -10/11 share the ability to induce ERK activation, that this is regulated by integrin {alpha}6A{beta}1, and suggest a novel role for dystroglycan-binding laminin domains as suppressors of this activation.