Epidermal growth factor receptor (EGFR) regulates cell motility by directing actin cytoskeleton reorganisation through the Rho family of GTPases, such as Rac1, and guanine nucleotide exchange factors (GEFs), such as VAV2. Although EGFR endocytosis has been well studied, its role in cell migration remains unclear. In this issue (Pinilla-Macua, Surve and Sorkin, 2025), Alexander Sorkin and colleagues demonstrate that clathrin-mediated endocytosis (CME) of EGFR maintains VAV2-mediated Rac1 signalling in endosomes and is essential for EGF-induced cell motility. Using live-cell imaging of human oral squamous carcinoma HSC3 cells, the authors show that endogenous fluorescently labelled VAV2 co-endocytoses with EGFR into early and sorting endosomes following EGF stimulation. Notably, endogenous Rac1 also localises to EGFR-containing endosomes, underlining the endosome as a crucial site for sustained EGFR-VAV2-Rac1 signalling. Furthermore, depletion of the clathrin heavy chain significantly reduces Rac1 activation and impairs cell motility, highlighting the role of CME in this process. Together, these results distinguish the EGFR-VAV2-Rac1 axis from other plasma membrane signalling pathways, showing that it uniquely relies on endosomal localisation for sustained activation and signalling output.
