A Jnk–Rho–Actin remodeling positive feedback network directs Src-driven invasion

摘要

Current models of tumor cell invasion propose that oncogenic signaling converges upon key orchestrators of cytoskeletal dynamics, including c-Jun N-terminal kinase (Jnk) and RhoGTPase family members; these signals dynamically direct Actin remodeling proteins (ARPs) to catalyze the cytoskeletal changes required for migration. Src is a key driver of tumor aggression, metastasis and patient mortality. To clarify how Src regulates Actin dynamics to promote invasive migration, we performed a genetic modifier screen in a Drosophila model of invasion. Nine genes linked to Actin dynamics were identified that mediate invasion in situ . We found that ARPs were required for many oncogenic effects of Src including Mmp1 expression and initiation of apoptosis. Surprisingly, they were also regulators of Jnk pathway activity: both Src and the small GTPase Rho1 activated Jnk in a manner dependent on ARPs during invasion. Our results suggest that ARPs are not simply downstream executors of signal transduction pathways. Rather, they participate in a positive feedback network involving canonical oncogenic signaling pathways that promote tumor invasion.