Rab5 induces Rac-independent lamellipodia formation and cell migration

Rab5 is a regulatory GTPase of vesicle docking and fusion that is involved in receptor-mediated endocytosis and pinocytosis. Introduction of active Ra b5 in cells stimulates the rate of endocytosis and vesicle fusion, resultin g in the formation of large endocytic vesicles, whereas dominant negative R ab5 inhibits vesicle fusion. Here we show that introduction of active Rab5 in fibroblasts also induced reorganization of the actin cytoskeleton but no t of microtubule filaments, resulting in prominent lamellipodia formation. The Rab5-induced lamellipodia formation did not require activation of PIS-K or the GTPases Ras, Rac, Cdc42, or Rho, which are all strongly implicated in cytoskeletal reorganization. Furthermore, lamellipodia formation by insu lin, Ras, or Pac was not affected by expression of dominant negative Rab5. In addition, cells expressing active Rab5 displayed a dramatic stimulation of cell migration, with the lamellipodia serving as the leading edge. Both lamellipodia formation and cell migration were dependent on actin polymeriz ation but not on microtubules. These results demonstrate that Rab5 induces lamellipodia formation and cell migration and that the Rab5-induced lamelli podia formation occurs by a novel mechanism independent of, and distinct fr om, PD-K, Ras, or Rho-family GTPases. Thus, Rab5 can control not only endoc ytosis but also actin cytoskeleton reorganization and cell migration, which provides strong support for an intricate relationship between these proces ses.