title: Cdc42 and the Rho GEF intersectin-1 collaborate with Nck to promote N-WASP-dependent actin polymerisation.
abstract: Vaccinia virus enhances its cell-to-cell spread by inducing Arp2/3-dependent actin polymerisation. This process is initiated by Src- and Abl-mediated phosphorylation of the viral transmembrane protein A36, leading to recruitment of a signalling network consisting of Grb2, Nck, WIP and N-WASP. Nck is a potent activator of N-WASP-Arp2/3-dependent actin polymerisation. However, recent observations demonstrate that an interaction between Nck and N-WASP is not required for vaccinia actin tail formation. We found that Cdc42 cooperates with Nck to promote actin tail formation by stabilising N-WASP beneath the virus. Cdc42 activation is mediated by the Rho guanine-nucleotide-exchange factor (GEF) intersectin-1 (ITSN1), which is recruited to the virus prior to its actin-based motility. Moreover, Cdc42, ITSN1 and N-WASP function collaboratively in a feed-forward loop to promote vaccinia-induced actin polymerisation. Outside the context of infection, we demonstrate that ITSN1 also functions together with Cdc42, Nck and N-WASP during phagocytosis mediated by the Fc gamma receptor. Our observations suggest that ITSN1 is an important general regulator of Cdc42-, Nck- and N-WASP-dependent actin polymerisation.
authors.affiliation: Cell Motility Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Humphries
authors.forename: Sara K
authors.initials: SK
authors.lastname: Donnelly
authors.forename: Michael
authors.initials: M
authors.lastname: Way
mesh_terms: D000199:Actins / Q000235:genetics* / Q000648:ultrastructure; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D051380:GRB2 Adaptor Protein / Q000235:genetics; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics* / Q000472:pathogenicity / Q000648:ultrastructure; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; C078332:Nck protein; D015513:Oncogene Proteins; C495771:WASL protein, human; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C115919:intersectin 1; D020764:cdc42 GTP-Binding Protein
keywords: Cdc42; ITSN1; Intersectin-1; N-WASP; Phagocytosis; Vaccinia