Cortactin recruits FMNL2 to promote actin polymerization and endosome motility in invadopodia formation.

Recently, invadopodia have been increasingly recognized as important drivers of local invasion and metastasis. Cortactin, as an actin-binding protein, is closely associated with invadopodia through interacting with proteins. Formin-like 2 (FMNL2), a member of diaphanous-related formins which act as nucleation factors, plays an important role in tumor progression. But whether cortactin can interact with FMNL2 to promote invadopodia formation and the role of FMNL2 in invadopodia formation are still unknown. Here we found that cortactin directly bound to FMNL2 and elevated the activities of actin polymerization and recycling endosome motility. FMNL2 was necessary for invadopodia formation and function in CRC cells. The interaction of cortactin and FMNL2 could further promote the invadopodia formation and matrix degradation. The stimulation of EGF/cdc42 enhanced the combination of cortactin and FMNL2 to intensify the numbers of invadopodia and the degrees of matrix degradation. In vivo, induction of invadopodia formation via cortactin is essential for the ability of FMNL2 to promote CRC metastasis. Furthermore, up-regulations of FMNL2 and cortactin were highly linked in CRC tissues. Collectively, our work demonstrates a brand-new mechanism of cortacin and FMNL2 at invadopodia in CRC.