title: Syndecan-4 phosphorylation is a control point for integrin recycling.
abstract: Precise spatiotemporal coordination of integrin adhesion complex dynamics is essential for efficient cell migration. For cells adherent to fibronectin, differential engagement of α5β1 and αVβ3 integrins is used to elicit changes in adhesion complex stability, mechanosensation, matrix assembly, and migration, but the mechanisms responsible for receptor regulation have remained largely obscure. We identify phosphorylation of the membrane-intercalated proteoglycan syndecan-4 as an essential switch controlling integrin recycling. Src phosphorylates syndecan-4 and, by driving syntenin binding, leads to suppression of Arf6 activity and recycling of αVβ3 to the plasma membrane at the expense of α5β1. The resultant elevation in αVβ3 engagement promotes stabilization of focal adhesions. Conversely, abrogation of syndecan-4 phosphorylation drives surface expression of α5β1, destabilizes adhesion complexes, and disrupts cell migration. These data identify the dynamic spatiotemporal regulation of Src-mediated syndecan-4 phosphorylation as an essential switch controlling integrin trafficking and adhesion dynamics to promote efficient cell migration.
authors: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors: Mark R
authors: MR
authors: Morgan
authors: Hellyeh
authors: H
authors: Hamidi
authors: Mark D
authors: MD
authors: Bass
authors: Stacey
authors: S
authors: Warwood
authors: Christoph
authors: C
authors: Ballestrem
authors: Martin J
authors: MJ
authors: Humphries
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D059027:Recycling; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D053671:Syndecan-4 / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; C508304:SDC4 protein, human; D053671:Syndecan-4; D014443:Tyrosine; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human