Synergism among lysophosphatidic acid, β₁A integrins, and epidermal growth factor or platelet-derived growth factor in mediation of cell migration

GD25 cells lacking the β₁ integrin subunit or expressing f₁A with certain cytoplasmic mutations have poor directed cell migration to platelet- derived growth factor (PDGF) or epidermal growth factor (EGF), ligands of receptor tyrosine kinases, or to lysophosphatidic acid (LPA), a ligand of G- protein-coupled receptors (Sakai, T., Zhang, Q., Fassler, R., and Mosher, D. F. (1998) J. Cell Biol. 141,527-538 and Sakai, T., Peyruchaud, O., Fassler, R., and Mosher, D. F. (1998) J. Biol. Chem. 273, 1937819382). We demonstrate here that LPA synergizes with signals induced by β₁A integrins and ligated EGF or PDGF receptors to modulate migration. When LPA was mixed with EGF or PDGF, migration was greater than with EGF or PDGF alone. The enhancement was greater for β₁-A-expressing cells than for β₁-null cells. Cells expressing β₁A with mutations of prolines or tyrosines in conserved cytoplasmic NPXY motifs had blunted migratory responses to mixtures of LPA and EGF or PDGF. The major effects on β₁A-expressing cells of LPA when combined with EGF or PDGF were to sensitize cells so that maximal responses were obtained with >10-fold lower concentrations of growth factor and increase the chemokinetic component of migration. Sensitization by LPA was lost when cells were preincubated with pertussis toxin or C3 exotransferase. There was no evidence for transactivation or sensitization of receptors for EGF or PDGF by LPA. EGF or PDGF and LPA caused activation of mitogen- activated protein kinase by pertussis toxin-insensitive and -sensitive pathways respectively, but activation was not additive. These findings indicate that signaling pathways initiated by the cytoplasmic domains of ligated β₁A integrins and tyrosine kinase receptors interact with signaling pathways initiated by LPA to facilitate directed cell migration.