Biological analysis of signal transduction of Rho-Rho kinase

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During the course of this project, we elucidated the three novel function of molecular switch Rho-ROCK signaling. Firstly, collaborating with orthopedic professor Dr. Yoshikawa, Osaka University medical school, we found that the inhibitor for ROCK accelerate the bone formation induced by bone morphogenetic protein (BMP) without affecting the bone metabolism in animal. Employing several undifferentiated mesenchymal cell lines, it revealed that Rho-ROCK signaling negatively regulated the expression of BMP, thus the ROCK inhibitor released such inhibition leading to the enhancement of osteoblastic differentiation (3). We further analyzed the signaling of osteoblastic differentiation and found that MEK-MAPK signaling also negatively regulated the osteoblastic signaling, and that the specific inhibitor for MEK1 (PD98059) enhanced bone formation both in vitro and in vivo (6). Future study for clinical application for these results is currently undertaken. Secondary, collaborating with Spanis … More h professor Dr. Sanchez Madrid, we analyzed the signaling for chemokine (SDF-1α)-induced lymphocyte chemotaxis and found that Rho-ROCK-myosin (molecular motor) signaling plays a pivotal role for that migration similar to that of cancer invasion, which we have already reported previously. We also found that Rho-ROCK signaling involved microtubule dynamics in lymphocytes using same system (5). Since lymphocyte migration is critical for immune response, our results open a new field to control the immune response via the modulation of migration of lymphocytes. Lastly, collaborating with Dr. Nishimura, Kyusyu University, we found that Rho-ROCK signaling control lysosomal vesicle trafficking via changing the microtubule dynamics (1, 7). The mechanism for intracellular trafficking is now hot field, since it regulated the number of cellular function and one of the best molecular targets for the clinical therapy. Our results shed light to the critical function of cytoskeletal change induced by Rho-ROCK on the vesicle trafficking and pharmacological manipulation of such system for the treatment of several diseases including devastating cancer. Less