Constitutive phosphorylation of a Rac GAP MgcRacGAP is implicated in v-Src-induced transformation of NIH3T3 cells |
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| Authors: | Noriko Doki Toshiyuki Kawashima Yasushi Nomura Akiho Tsuchiya Chitose Oneyama Tsuyoshi Akagi Yoshihisa Nojima Toshio Kitamura |
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| Affiliation: | Division of Cellular Therapy, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo;;Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gumma;;Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka;;KAN Research Institute, Inc. Kobe MI R&D Center, Chuo-ku, Kobe, Japan |
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| Abstract: | MgcRacGAP plays critical roles in cell division through regulating Rho family small GTPases. As we previously reported, phosphorylation of MgcRacGAP on serine 387 (S387) is induced by Aurora B kinase at the midbody during cytokinesis, which is a critical step of cytokinesis. Phosphorylation of S387-MgcRacGAP converts it from RacGAP to RhoGAP, leading to completion of cytokinesis. Here we show that MgcRacGAP is prominently phosphorylated on S387 even in the interphase of v-Src-transformed NIH3T3 cells in the cytoplasm, but not in the interphase of parental NIH3T3 or H-RasV12-transformed NIH3T3 cells. Interestingly, levels of phosphorylation on S387 (pS387) correlated with soft agar colony-forming abilities of v-Src-transformed NIH3T3 cells. Expression of a phosphorylation-mimic mutant MgcRacGAP-S387D enhanced colony formation of v-Src-transformed NIH3T3 cells. Surprisingly, a Rac1 inhibitor but not kinase inhibitors including Aurora B kinase inhibitor specifically inhibited phosphorylation of S387-MgcRacGAP in v-Src-transformed NIH3T3 cells, suggesting the v-Src-induced pathological positive feedback mechanisms towards Rac1 activation using pS387-MgcRacGAP. These results indicated the difference in the mechanisms between v-Src- and H-RasV12-induced transformation, and should shed some light on pathological roles of disordered phosphorylation of MgcRacGAP at S387 in v-Src-induced cell transformation. ( Cancer Sci 2009; 100: 1675–1679) |
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