Signal Transduction and Cellular Functions of the Small GTPase Rho and its Effectors

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Effectors for the small GTPase Rho were determined, and signal tranuction pathways from Rho to the reorganization of the actin cytoskeleton were identified. (1) We identified that ROCK-kinase, that is activated downstream of Rho, moblizes at least three pathways to regulate the actin cytoskeleton, one being phsporylaiton and inacitvation of myosin phosphatas to increase the myosin-based contractility, the second phosphorylaiton and acivaton of LIM-linase leading to inactivation of actin depolymerizing activity of cofilin, and the third phosphorylation of type I NaH exchanger. We further showed that these Rho-ROCK pathways are impliated in elicitation of hypertension and invasion and metastasis of tumor cells. (2) We identified p140mDia as a novel Rho effector protein. This protein binds profiin through its FH1 region and regulate alignment of microtubules through its FH2 region, and thereby integrate the organization of the actin cytoskeleton and microtubules. We showed that this action of mDia is essential in Rho-induced inducion and alignment of stress fibers. (3) We identified Citron-kinase, and showed that it works as a Rho effector in cytokinesis. We heve also developed a pull-down assay for GTP-Rho, and showed that ECT2 is a Rho exchanger working in cytokinesis. (4) We identified ropporin as a binding protein of rhophilin, and showed that the two proteins together localize in the sperm tail. We also showed that ropporin makes a homo dimer and binds to another sperm protein, AKAP-110.