Restoration of β1A integrins is required for lysophosphatidic acid-induced migration of β1-null mouse fibroblastic cells

Cells lacking the beta(1) integrin subunit or expressing beta(1)A with certain cytoplasmic mutations have poor directed cell migration to platelet-derived growth factor or epidermal growth factor, ligands of receptor tyrosine kinases (Sakai, T., Zhang, Q., FHssler, 8, and Mosher, D. F, (1998) J. Cebl Biol. 141, 527-538). We investigated the effect of expression of beta(1)A integrins on lysophosphatidic acid (LPA)-induced migration of fibroblastic cells derived from beta(1)-null mouse embryonic stem cells. These cells expressed edg-2, a G-protein-linked receptor for LPA, as well as the related edg-1 receptor. Cells expressing wild type beta(1)A demonstrated enhanced cell migration across filters coated with gelatin or adhesive proteins in response to LPA, whereas beta(1)-deficient cells lacked LPAinduced cell migratory ability. Checkerboard analyses indicated that LPA causes both chemotaxis and chemokinesis of beta(1)-replete cells. Cells expressing beta(1)A with mutations of prolines or tyrosines in conserved cytoplasmic NPXY motifs, threonine in the inter-motif sequence, or a critical aspartic acid in the extracellular domain had low migratory responses to LPA. These findings indicate that active beta(1)A integrin is required for cell migration induced by LPA and that the cytoplasmic domain of ligated beta(1)A interacts with pathways that are common to both receptor tyrosine kinase and G-protein-linked receptor signaling.