A Syndecan-4 Hair Trigger Initiates Wound Healing through Caveolin- and RhoG-Regulated Integrin Endocytosis

Summary Cell migration during wound healing requires adhesion receptor turnover to enable the formation and disassembly of cell-extracellular matrix contacts. Although recent advances have improved our understanding of integrin trafficking pathways, it is not known how extracellular ligand engagement controls receptor dynamics. Using atomic force microscopy, we have measured cell avidity for fibronectin and defined a mechanism for the outside-in regulation of α5β1-integrin. Surprisingly, adhesive strength was attenuated by the syndecan-4-binding domain of fibronectin due to a rapid triggering of α5β1-integrin endocytosis. Association of syndecan-4 with PKCα was found to trigger RhoG activation and subsequent dynamin- and caveolin-dependent integrin uptake. Like disruption of syndecan-4 or caveolin, gene disruption of RhoG in mice was found to retard closure of dermal wounds due to a migration defect of the fibroblasts and keratinocytes of RhoG null mice. Thus, this syndecan-4-regulated integrin endocytic pathway appears to play a key role in tissue repair.
Graphical Abstract Highlights ► Syndecan-4 engagement mobilizes cells by reducing avidity for extracellular matrix ► Syndecan-4 induces caveolin-mediated endocytosis rather than inactivation of integrin ► Matrix ligands of syndecan-4 cause RhoG activation, which triggers endocytosis ► Gene disruption of syndecan-4, RhoG, or caveolin-1 results in compromised wound healing