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.