Competition between TIAM1 and Membranes Balances Endophilin A3 Activity in Cancer Metastasis

Normal cells acquire aggressive behavior by modifying signaling pathways. For instance, alteration of endocytosis profoundly impacts both proliferation and migration during tumorigenesis. Here we investigate the mechanisms that enable the endocytic machinery to coordinate these processes. We show that a membrane curvature-sensing protein, endophilin A3, promotes growth and migration of colon cancer cells through two competing mechanisms: an endocytosis pathway that is required for proliferation and a GTPase regulatory pathway that controls cell motility. EndoA3 stimulates cell migration by binding the Rac GEF TIAM1 leading to activation of small GTPases. Competing interactions of EndoA3 with membrane versus TIAM1 modulate hyperproliferative and metastatic phenotypes. Disruption of EndoA3-membrane interactions stimulates TIAM1 and small GTPases in vitro, and further promotes pro-metastatic phenotypes in vivo. Together, these results uncover a coupling mechanism, by which EndoA3 promotes growth and migration of colon cancers, by linking membrane dynamics to GTPase regulation. Poudel et al. show that endophilin A3 (EndoA3) modulates proliferation and migration of colorectal cancer cells using two distinct pathways, i.e., EndoA3 facilitates cell proliferation by enhancing endocytosis, and it promotes migration by activating TIAM1 and Rac1. Modulation of the two pathways tunes tumor progression in vivo.