Biological analysis of signal transduction of Rho-Rho kinase

Rho-Rho激酶信号转导的生物学分析

• 批准号: 12680648
• 负责人: ITOH Kazuyuki
• 金额: $ 2.43万
• 依托单位: Osaka Medical Center for Cancer and Cardiovascular Diseases
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680648/
• 关键词: Rho; Rho kinase (ROCK); BMP; Bone formation; chemokine; lymphocyte; lysosome; intracellular trafficking; コラーゲン; stromal cell; Rho kinase(ROCK)

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

在本项目的研究过程中，我们阐明了分子开关Rho-ROCK信号的三个新功能。首先，我们与大坂大学医学院骨科教授Yoshikawa博士合作，发现ROCK抑制剂加速骨形态发生蛋白（BMP）诱导的骨形成，而不影响动物的骨代谢。采用几种未分化的间充质细胞系，结果显示Rho-ROCK信号传导负调控BMP的表达，因此ROCK抑制剂释放这种抑制作用，导致成骨细胞分化的增强（3）。我们进一步分析了成骨细胞分化的信号传导，发现MEK-MAPK信号传导也负调节成骨细胞信号传导，并且MEK 1的特异性抑制剂（PD 98059）在体外和体内均增强骨形成（6）。目前正在对这些结果进行进一步的临床应用研究。中学，与Spanis合作 ...更多信息 在Sanchez马德里教授的研究中，我们分析了趋化因子（SDF-1α）诱导的淋巴细胞趋化性的信号传导，发现Rho-ROCK-肌球蛋白（分子马达）信号传导在这种迁移中起着关键作用，类似于我们以前报道的癌症侵袭。我们还发现Rho-ROCK信号传导涉及使用相同系统的淋巴细胞中的微管动力学（5）。由于淋巴细胞迁移是免疫反应的关键，我们的研究结果开辟了一个新的领域，通过调节淋巴细胞的迁移来控制免疫反应。最后，与九州大学Nishimura博士合作，我们发现Rho-ROCK信号通过改变微管动力学来控制溶酶体囊泡运输（1，7）。细胞内转运的机制是目前研究的热点，因为它调节细胞功能的数量，是临床治疗的最佳分子靶点之一。我们的研究结果揭示了Rho-ROCK诱导的细胞骨架变化对囊泡运输的关键作用以及对该系统的药理学操作，用于治疗包括毁灭性癌症在内的多种疾病。少

项目成果

Manzanares, MV., Cabrero JR., Rey, M., Martinez, MR., Ursa, A., Itoh. K. and Madrid, FS.: "A role for the Rho-p160Rho coiled-coil kinase axis in the chemokine stromal cell-derived factor-lα-induced lymphocyte actomyosin and microtubular organization and c

Manzanares, MV.、Cabrero JR.、Rey, M.、Martinez, MR.、Ursa, A.、Itoh. K. 和Madrid, FS.：“Rho-p160Rho 卷曲螺旋激酶轴在趋化因子中的作用基质细胞源性因子lα诱导的淋巴细胞肌动球蛋白和微管组织及c

Saeki,Y.,Hazeki,K.,Hazeki,O.,Ui,M.,Itoh,K.,Matsumoto,M.,Toyoshima,K.,Akedo,H.& Seya,Y.: "Participation of a MEK-independent pathway in MAP kinase activation and modulation of cell growth in mouse hepatoma cell lines"Int.J.Mol.Med. 6. 155-160 (2000)

佐伯Y.、Hazeki,K.、Hazeki,O.、Ui,M.、Itoh,K.、松本M.、丰岛K.、Akedo,H.

Itoh,K.and Yoshioka,K: "Key molecules that regulate breast cancer cells to invade new tissues"ASCB Press Book. 7 (2000)

Itoh,K. 和 Yoshioka,K：“调节乳腺癌细胞侵入新组织的关键分子”ASCB 出版社书。

Itoh, K., Yoshioka, K., Nakase, T., Yoshikawa, H.: "Stimulation of Bone Formation by Rho-associated Kinase Inhibitor"J.Bone Miner.Res.. 16. 235 (2001)

Itoh, K.、Yoshioka, K.、Nakase, T.、Yoshikawa, H.：“Rho 相关激酶抑制剂刺激骨形成”J.Bone Miner.Res.. 16. 235 (2001)

Higuchi, C., Myoui, A., Hashimoto, N., Kuriyama, K., Yoshioka, K., Yoshikawa, H., Itoh, K.: "Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of extracellular matrix"J.Bone Miner.Res.. 17. 1785-179

Higuchi, C.、Myoui, A.、Hashimoto, N.、Kuriyama, K.、Yoshioka, K.、Yoshikawa, H.、Itoh, K.：“持续抑制 MAPK 信号传导可促进早期成骨细胞分化和细胞外矿化