Title: Synaptojanin 2, a novel Rac1 effector that regulates clathrin-mediated endocytosis
Abstract: The small GTPase Rac has been implicated in a wide range of cellular processes, including the organization of the actin cytoskeleton, transcriptional control and endocytic vesicle trafficking [1Hall A Rho GTPases and the actin cytoskeleton.Science. 1998; 279: 509-514Crossref PubMed Scopus (5068) Google Scholar, 2Westwick JK Lambert QT Clark GJ Symons M Van Aelst L Pestell RG Der CJ Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways.Mol Cell Biol. 1997; 17: 1324-1335Crossref PubMed Scopus (374) Google Scholar, 3Lamaze C Chuang TH Terlecky LJ Bokoch GM Schmid SL Regulation of receptor-mediated endocytosis by Rho and Rac.Nature. 1996; 382: 177-179Crossref PubMed Scopus (321) Google Scholar]. The signaling components that mediate these functions downstream of Rac largely remain to be identified. In this study, we have identified synaptojanin 2, a polyphosphoinositide phosphatase as a novel Rac1 effector. Synaptojanin 2 directly and specifically interacts with Rac1 in a GTP-dependent manner. Expression of constitutively active Rac1 caused the translocation of synaptojanin 2 from the cytoplasm to the plasma membrane. Both activated Rac1 and a membrane-targeted version of synaptojanin 2 inhibited endocytosis of the epidermal growth factor (EGF) and transferrin receptors, a process that is known to be dependent on polyphosphoinositide lipids. Endocytosis of growth factor receptors is thought to play an important role in the regulation of cell proliferation. Thus, these results suggest that synaptojanin 2 may mediate the inhibitory effect of Rac1 on endocytosis and could contribute to Rac1-mediated control of cell growth.