Reciprocal regulation of Solo and Src orchestrates Src trafficking to promote mesenchymal cell migration

Rho GTPases are key regulators of cell motility and membrane trafficking, influencing critical processes such as epithelial-mesenchymal transition (EMT). Among them, the small GTPase RhoB plays a pivotal role, but the mechanisms underlying its regulation remain largely unclear. We have previously identified the Rho guanine nucleotide exchange factor (RhoGEF) Solo (ARHGEF40) as a regulator of endosomal RhoB in epithelial cells. Here, we find that Solo is upregulated in breast cancer cells with high EMT scores and promotes cell motility through its RhoGEF activity. Solo’s ability to enhance migration is further regulated by phosphorylation at tyrosine 242, mediated by the proto-oncogene Src. By combining high-resolution imaging with photoconversion assays, we further demonstrate that Solo regulates Src trafficking dynamics, localization, and consequently signaling at focal adhesions. Together, our data identify Solo as a novel feedback regulator of Src and a key driver of the motility of breast cancer cells with mesenchymal characteristics.