Sci. STKE, 19 September 2006
Phospholipids Phosphatidylserine Recruits Rac1
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005, USA
Rac1 is a member of the Rho family of guanosine triphosphatases (GTPases) and is involved in stimulating membrane ruffling and cell migration. Finkielstein et al. show, using liposome-binding assays, nuclear magnetic resonance assays, and lipid overlay assays, that purified Rac1, either prenylated or nonprenylated, GTP-bound or GDP-bound, interacts specifically with phosphatidylserine, an anionic lipid that is abundant on the inner leaflet of the plasma membrane. Surface plasmon resonance assays demonstrated that prenylated Rac1 had a higher affinity for phosphatidylserine than did nonprenylated Rac1. The interaction required the polybasic motif (PBM), and mutation of a lysine and an arginine (K186A/R187A) abolished Rac1 binding to phosphatidylserine. Cells expressing the K186A/R187A mutant showed an altered distribution of Rac1 that was located in cytosolic puncta, which may reflect binding to internal membranes, instead of the plasma membrane. Exposure of cells transfected with wild-type or various Rac1 mutants to phosphatidylserine caused membrane ruffling, formation of filopodia, and reduction in actin stress fibers and stimulated cell migration in a wound assay. Each response required Rac1 GTPase activity and an intact PBM. Exposure of the transfected cells to phosphatidylserine stimulated the translocation of Rac1 to the plasma membrane, Rac1 GTP loading, activation of Cdc42 (a Rho GTPase that is downstream of Rac1), and activation of the mitogen-activated protein kinase kinase (MEK1). The authors propose that, as with Src, Raf-1, and KRas4B, the PBM allows targeting of Rac1 to specific regions of the plasma membrane through the interactions with phosphatidylserine, thereby facilitating the interaction of Rac1 with its regulators and effectors.
C. V. Finkielstein, M. Overduin, D. G. S. Capelluto, Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1. J. Biol. Chem. 281, 27317-27326 (2006). [Abstract] [Full Text]
Citation: N. R. Gough, Phosphatidylserine Recruits Rac1. Sci. STKE 2006, tw323 (2006).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882