Synergism among lysophosphatidic acid, beta(1)A integrins, and epidermal growth factor or platelet-derived growth factor in mediation of cell migration

GD25 cells lacking the beta(1) integrin subunit or expressing beta(1)A with certain cytoplasmic mutations have poor directed cell migration to platele t 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,, Fas sler, R,, and Mosher, D, F, (1998) J, Biol, Chem, 273, 19378-19382), We dem onstrate here that LPA synergizes with signals induced by beta(1)A integrin s and ligated EGF or PDGF receptors to modulate migration. When LPA was mix ed with EGF or PDGF, migration was greater than with EGF or PDGF alone. The enhancement was greater for beta(1)A-expressing cells than for beta(1)-nul l cells. Cells expressing beta(1)A with mutations of prolines or tyrosines in conserved cytoplasmic NPXY motifs had blunted migratory responses to mix tures of LPA and EG:F or PDGF, The major effects on beta(1)A-expressing cel ls of LPA when combined with EC:F or PDGF were to sensitize cells so that m aximal 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 ex otransferase. 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 -sensi tive pathways respectively, but activation was not additive. These findings indicate that signaling pathways initiated by the cytoplasmic domains of l igated beta(1)A integrins and tyrosine kinase receptors interact with signa ling pathways initiated by LPA to facilitate directed cell migration.