ARHGEF5 and cancer: The formation of podosomes/invadopodia has been implicated in the invasive and metastatic potential of cancer cells.22, 23, 37 Src activity is necessary for podosome formation, and active Rho, which localizes to podosomes, is required for the assembly of these structures.38 We identified ARHGEF5 as a GEF responsible for the activation of podosomal Rho,21 and an extended analysis using ARHGEF5 knockout mouse embryonic fibroblasts corroborated that ARHGEF5 accumulates in podosomes and is essential for Src-induced podosome formation (Supplementary Figure S4).