Syndecan-4 Phosphorylation Is a Control Point for Integrin Recycling

• Published in: Developmental cell Vol. 24; no. 5; pp. 472 - 485
• Main Authors: Morgan, Mark R., Hamidi, Hellyeh, Bass, Mark D., Warwood, Stacey, Ballestrem, Christoph, Humphries, Martin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.03.2013; Cell Press
• Subjects: adhesion; ADP-Ribosylation Factor 6; ADP-Ribosylation Factors - metabolism; Amino Acid Sequence; Blotting, Western; Cell Adhesion - physiology; Cell Membrane - metabolism; cell movement; Cell Movement - physiology; Cells, Cultured; Cytosol - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; fibronectins; Flow Cytometry; Fluorescent Antibody Technique; Focal Adhesions - metabolism; Humans; Immunoprecipitation; Integrin alpha5beta1 - metabolism; Integrin alphaVbeta3 - metabolism; integrins; Molecular Sequence Data; Phosphorylation; plasma membrane; Protein Binding; proteoglycans; Recycling; Sequence Homology, Amino Acid; Signal Transduction; Syndecan-4 - metabolism; Tyrosine - metabolism
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2013.01.027

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. [Display omitted] ► c-Src phosphorylates syndecan-4 in response to extracellular stimuli ► Syndecan-4 phosphorylation and engagement regulate Arf6 activity ► Syndecan-4-mediated Arf6 activity regulates differential integrin recycling ► Syndecan-4-mediated integrin recycling controls FA dynamics and cell migration Efficient cell migration requires dynamic coordination of cell-matrix interactions, in part through precise spatiotemporal control of integrin adhesion dynamics. Morgan et al. show that phosphorylation of the extracellular matrix receptor syndecan-4 acts as a molecular switch, differentially directing either α5β1 or αVβ3 integrin recycling in the control of adhesion dynamics.