Cdc42 regulates Cdc42EP3 function in cancer-associated fibroblasts

Rho family GTPases such as Cdc42 are key regulators of essential cellular processes through their effects on cytoskeletal dynamics, signaling and gene expression. Rho GTPases modulate these functions by engaging a wide variety of downstream effectors. Among these effectors is the largely understudied Cdc42EP/BORG family of Cdc42 effectors. BORG proteins have been linked to actin and septin regulation, but their role in development and disease is only starting to emerge. Recently, Cdc42EP3/BORG2 was shown to coordinate actin and septin cytoskeleton rearrangements in cancer-associated fibroblasts (CAFs). Interestingly, Cdc42EP3 expression potentiated cellular responses to mechanical stimulation leading to signaling and transcriptional adaptations required for the emergence of a fully activated CAF phenotype. These findings uncover a novel role for the BORG/septin network in cancer. Here, we demonstrate that Cdc42EP3 function in CAFs relies on tight regulation by Cdc42.