title: β-Arrestin 1-dependent regulation of Rap2 is required for fMLP-stimulated chemotaxis in neutrophil-like HL-60 cells.
abstract: β-Arrestins have emerged as key regulators of cytoskeletal rearrangement that are required for directed cell migration. Whereas it is known that β-arrestins are required for formyl-Met-Leu-Phe receptor (FPR) recycling, less is known about their role in regulating FPR-mediated neutrophil chemotaxis. Here, we show that β-arrestin 1 (ArrB1) coaccumulated with F-actin within the leading edge of neutrophil-like HL-60 cells during chemotaxis, and its knockdown resulted in markedly reduced migration within fMLP gradients. The small GTPase Ras-related protein 2 (Rap2) was found to bind ArrB1 under resting conditions but dissociated upon fMLP stimulation. The FPR-dependent activation of Rap2 required ArrB1 but was independent of Gαiactivity. Significantly, depletion of either ArrB1 or Rap2 resulted in reduced chemotaxis and defects in cellular repolarization within fMLP gradients. These data strongly suggest a model in which FPR is able to direct ArrB1 and other bound proteins that are required for lamellipodial extension to the leading edge in migrating neutrophils, thereby orientating and directing cell migration.
authors: Chemotaxis Signal Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA; and nidhi_gera@hms.harvard.edu.
authors: Nidhi
authors: N
authors: Gera
authors: Department of Neurology, Division of Neuro-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors: Kenneth D
authors: KD
authors: Swanson
authors: Chemotaxis Signal Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA; and tjin@niaid.nih.gov.
authors: Tian
authors: T
authors: Jin
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006801:Humans; D008954:Models, Biological; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071559:beta-Arrestin 1 / Q000378:metabolism*; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D002630:Chemotactic Factors; D000071559:beta-Arrestin 1; D009240:N-Formylmethionine Leucyl-Phenylalanine; C116756:RAP2A protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020668:rap GTP-Binding Proteins
keywords: GPCR; GTPase; cell migration