title: A Jnk-Rho-Actin remodeling positive feedback network directs Src-driven invasion.
abstract: 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.
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: V A
authors.initials: VA
authors.lastname: Rudrapatna
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bangi
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Cagan
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D025461:Feedback, Physiological; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins