title: Abelson-interactor-1 promotes WAVE2 membrane translocation and Abelson-mediated tyrosine phosphorylation required for WAVE2 activation.
abstract: WAVE2 is a member of the Wiskott-Aldrich syndrome protein family of cytoskeletal regulatory proteins shown to link Rac activation to actin remodeling via induction of Arp 2/3 activity. WAVE2 is thought to be regulated by its positioning in a macromolecular complex also containing the Abelson-(Abl) interactor-1 (Abi-1) adaptor, but the molecular basis and biologic relevance of WAVE2 inclusion in this complex are ill defined. Here we show that Abi-1 binding to WAVE2 is mediated by discrete motifs in the Abi-1 coiled-coil and WAVE2 WAVE-homology domains and increases markedly in conjunction with Abi-1-WAVE2 translocation and colocalization at the leading edge in B16F1 cells after fibronectin stimulation. Abi-1 also couples WAVE2 to Abl after cell stimulation, an interaction that triggers Abl membrane translocation with WAVE2, Abi-1, and activated Rac, as well as Abl-mediated tyrosine phosphorylation and WAVE2 activation. By contrast, mutation of tyrosine residue Y150, identified here as the major site of Abl-mediated WAVE2 tyrosine phosphorylation, as well as disruption of WAVE2-Abi-1 binding, impairs induction of WAVE2-driven actin polymerization and its membrane translocation in association with activated Rac. Similarly, WAVE2 tyrosine phosphorylation and induction of membrane actin rearrangement are abrogated in fibroblasts lacking the Abl family kinase. Together, these data reveal that Abi-1-mediated coupling of Abl to WAVE2 promotes Abl-evoked WAVE2 tyrosine phosphorylation required to link WAVE2 with activated Rac and with actin polymerization and remodeling at the cell periphery.
authors.affiliation: Departments of Medicine, Immunology, Medical Genetics, and Microbiology, University of Toronto and The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.forename: Jinyi
authors.initials: J
authors.lastname: Zhang
authors.forename: Karen
authors.initials: K
authors.lastname: Badour
authors.forename: Enrico
authors.initials: E
authors.lastname: Arpaia
authors.forename: Spencer
authors.initials: S
authors.lastname: Freeman
authors.forename: Pam
authors.initials: P
authors.lastname: Cheung
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Katherine
authors.initials: K
authors.lastname: Siminovitch
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family
chemical_list: C513733:ABI1 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl