Regulation of c‐Met signaling by the tetraspanin KAI‐1/CD82 affects cancer cell migration

It has been proposed that the metastasis suppressor CD82/KAI‐1, which is a member of the tetraspanin superfamily, regulates biological activity by associating with cell surface receptors or proteins. We show a novel association between CD82 and the hepatocyte growth factor (HGF) receptor c‐Met. Although ectopic expression of CD82 in nonsmall cell lung carcinoma cells did not affect the tyrosine phosphorylation of c‐Met, these cells showed significant suppression of HGF‐induced lamellipodial protrusion and cell migration. CD82 selectively attenuated c‐Met signaling via the Ras‐Cdc42/Rac and the phosphatidylinositol 3‐kinase/Cdc42/Rac pathways. In contrast, another c‐Met signaling pathway that involves phosphatidylinositol 3‐kinase/Akt and phosphatidylinositol 3‐kinase/mitogen activated protein kinase was not affected by CD82. Signaling adapter proteins for c‐Met, such as Grb2 and p85, exhibited reduced association with c‐Met in cells that ectopically expressed CD82. These results indicate that the CD82‐c‐Met complex inhibits HGF‐induced cancer cell migration by the inactivation of small GTP‐binding proteins of the Rho family via c‐Met adapter proteins. © 2007 Wiley‐Liss, Inc.