title: Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1.
abstract: The Rho guanosine triphosphatases (GTPases) control cell shape and motility and are frequently overexpressed during malignant growth. These proteins act as molecular switches cycling between active GTP- and inactive GDP-bound forms. Despite being membrane anchored via their isoprenylated C termini, Rho GTPases rapidly translocate between membrane and cytosolic compartments. Here, we show that the Rho GTPase Rac1 preferentially interacts with phosphatidylserine (PS)-containing bilayers through its polybasic motif (PBM). Rac1 isoprenylation contributes to membrane avidity but is not critical for PS recognition. The similar protein Cdc42 (cell division cycle 42), however, only associates with PS when prenylated. Conversely, other Rho GTPases such as Rac2, Rac3, and RhoA do not bind to PS even when they are prenylated. Cell stimulation with PS induces translocation of Rac1 toward the plasma membrane and stimulates GTP loading, membrane ruffling, and filopodia formation. This stimulation also promotes Cdc42 activation and phosphorylation of mitogen-activated protein kinase through Rac1/PS signaling. Consequently, the PBM specifically directs Rac1 to effect cytoskeletal rearrangement and cell migration by selective membrane phospholipid targeting.
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
authors.forename: Carla V
authors.initials: CV
authors.lastname: Finkielstein
authors.forename: Michael
authors.initials: M
authors.lastname: Overduin
authors.forename: Daniel G S
authors.initials: DG
authors.lastname: Capelluto
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002465:Cell Movement; D006153:Guanosine Diphosphate / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D006801:Humans; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D010718:Phosphatidylserines / Q000737:chemistry*; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010718:Phosphatidylserines; C107953:RAC1 protein, human; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein