EGF-stimulated Activation Of Rab35 Regulates RUSC2-GIT2 Complex Formation To Stabilize GIT2 During Directional Lung Cancer Cell Migration

Non-small cell lung cancer(NSCLC)remains one of the most metastasizing tumour.And,directional cells migration is critical for targeting tumor metastasis.GIT2 has been known as a multidomain protein that binds to Paxillin to control cell polarization and directional migration.However,the molecular mechanisms underlying roles of GIT2 in controlling cell polarization and directional migration remain elusive.Here we demonstrated GIT2 control cell polarization and directional migration to some extent dependent on the regulation of Golgi through RUSC2.RUSC2 interacts with SHD of GIT2 in lung cancer cells,and stabilizes GIT2 to increase its phosphorylation by decreasing degradation.Knockdown of RUSC2 showed reduced stability GIT2,defective Golgi reorientation toward the wound edge and decreased directional migration.Moreover,short-term EGF stimulation can increase the interaction between RUSC2 and GIT2,prolonged stimulation leads to a decrease of their interaction through activating Rab35.Knockdown of Rab35 also showed reduced stability and phosphorylation of GIT2 and decreased cell migration.Taken together,our study indicated that RUSC2 participates in EGFR signaling and regulates lung cancer progression,and may be a new therapeutic target against lung cancer metastasis.