The Function Of JNK In RAP2 Mediated Celltransformation

Rap2, a Ras family small GTPase regulates a variety of cellular functions including cell proliferation, adhesion and migration through activatingits downstream effectors Raf, MAP4K4, TNIK, PARG, etc. Among these factors, MAP4K4, a member of STE20 family kinase is involved in the regulation of cell migration of multiple cancer cell lines. JNK, a downstream target regulated by MAP4K4 is found to correlate to the promoted migration of many carcinoma cells. In quiescent states, the inactivated JNK distributes over cytoplasm and nucleus, and once activated it translocates to the nucleus as well as to the plasma membrane, regulating apoptosis and cell migration. However, whether JNK could act downstream of Rap2 to regulate cell migration is recently unknown.In this paper, we report that the expression of JNK2, the negative regulator of activated JNK1, remarkably reduced in HEK293 cells expressing Rap2-12V, the active mutant of Rap2, and that the phosphorylationof JNK1 increased when transfected with Rap2. In addition, large fraction of JNK became accumulated to the nucleus of NIH3T3 cells when Rap2 was overexpressed in the cells,indicating that overexpressioin of Rap2 could promote the activation and translocation of JNK in the cells. Moreover, HEK293 cells overexpressing Rap2 showed faster migration rate than cells transfected with vector in response to serum gradient by transwell assay. The increased cell migration was significantly inhibited when the cells was treated with SP600125, the JNK specific inhibitor. Taken together, our results indicated that JNK could act as downstream of Rap2 to regulate cell migration.