The role of Epidermal Growth Factor Receptor (EGFR) trafficking in Syndecan-4-regulated migration

Epidermal growth factor receptor (EGFR) signaling is important for fibroblast migration and tissue repair. Upon EGF binding, EGFR forms asymmetric dimers and undergoes rapid internalization through clathrin-mediated and clathrin-independent endocytic pathways. The intracellular fate of EGFR-recycling or degradation-is highly dependent on extracellular ligand concentration, with low EGF levels favoring recycling and high concentrations promoting lysosomal degradation. While tyrosine phosphorylation initiates EGFR activation, serine/threonine phosphorylation provides additional regulatory control, particularly over receptor trafficking and turnover.
A transmembrane heparan sulfate proteoglycan named syndecan-4（SDC4） functions as a co-receptor for EGFR and is strongly induced during wound healing. SDC4 has been shown to activate protein kinase Cα (PKCα) and modulate downstream signaling events essential for directional cell migration. Despite evidence linking SDC4 to EGFR signaling, the mechanistic relationship between these two receptors especially in the context of endocytosis remains poorly defined.
In this study, we investigated the role of SDC4 in regulating EGFR trafficking and EGF induced fibroblast migration. We show that loss of SDC4 disrupts EGFR internalization and impairs phosphorylation following EGF stimulation. Mass spectrometry analysis revealed a broad effect of phosphorylation events in the absence of SDC4, suggesting that SDC4 is required for proper EGFR signals.
Our findings reveal a novel regulatory linking syndecan-4, PKCα, and EGFR, providing new insight into how extracellular matrix engagement shapes receptor-mediated signaling and cell migration. These results have implications for therapeutic strategies in wound healing, where EGF responsiveness may depend on SDC4 expression and function.