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

Cells lacking the β₁ integrin subunit or expressing β₁A 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., Fassler, R., and Mosher, D. F. (1998) J. Cell Biol. 141, 527-538). We investigated the effect of expression of β₁A integrins on lysophosphatidic acid (LPA)-induced migration of fibroblastic cells derived from β₁-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 β₁A demonstrated enhanced cell migration across filters coated with gelatin or adhesive proteins in response to LPA, whereas β₁-deficient cells lacked LPA-induced cell migratory ability. Checkerboard analyses indicated that LPA causes both chemotaxis and chemokinesis of β₁-replete cells. Cells expressing β₁A 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 β₁A integrin is required for cell migration induced by LPA and that the cytoplasmic domain of ligated β₁A interacts with pathways that are common to both receptor tyrosine kinase and G-protein-linked receptor signaling.