title: Abl interactor 1 (Abi-1) wave-binding and SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodium localization, and wave-1 levels.
abstract: The Abl interactor 1 (Abi-1) protein has been implicated in the regulation of actin dynamics and localizes to the tips of lamellipodia and filopodia. Here, we show that Abi-1 binds the actin nucleator protein Wave-1 through an amino-terminal Wave-binding (WAB) domain and that disruption of the Abi-1-Wave-1 interaction prevents Abi-1 from reaching the tip of the lamellipodium. Abi-1 binds to the Wave homology domain of Wave-1, a region that is required for translocation of Wave-1 to the lamellipodium. Mouse embryo fibroblasts that lack one allele of Abi-1 and are homozygous null for the related Abi-2 protein exhibit decreased Wave-1 protein levels. This phenotype is rescued by Abi-1 proteins that retain Wave-1 binding but not by Abi-1 mutants that cannot bind to Wave-1. Moreover, we uncovered an overlapping SNARE domain in the amino terminus of Abi-1 that interacts with Syntaxin-1, a SNARE family member. Further, we demonstrated that Abi-1 shuttles in and out of the nucleus in a leptomycin B (LMB)-dependent manner and that complete nuclear translocation of Abi-1 in the absence of LMB requires the combined inactivation of the SNARE, WAB, and SH3 domains of Abi-1. Thus, Abi-1 undergoes nucleocytoplasmic shuttling and functions at the leading edge to regulate Wave-1 localization and protein levels.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Duke University, Durham, NC 27710, USA.
authors.forename: Asier
authors.initials: A
authors.lastname: Echarri
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Lai
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Robinson
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Pendergast
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D050600:SNARE Proteins; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D051300:Wiskott-Aldrich Syndrome Protein Family
chemical_list: C513734:Abi1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D000954:Antigens, Surface; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; C494214:Stx1a protein, mouse; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; C495774:Wasf1 protein, mouse; D051300:Wiskott-Aldrich Syndrome Protein Family