Tohru Kataoka, Professor
M.D. Univ. of Tokyo, 1977; Ph.D. Grad. Sch. Osaka Univ., 1981; Instructor, Osaka Univ. Med. Sch., 1981-85; Visit. Scientist, Cold Spr. Harbor Lab., 1983-85; Staff Investigator 1985-86; Assist. Prof. of Cell. & Mol. Physiol., Harvard Med. Sch., 1986-89; Professor, Kobe Univ. Sch. Med., 1989- .
Dean, Kobe University Graduate School of Medicine / School of Medicine.,2013-

Research Field: Intracellular Signal Transduction Mechanisms, Oncogenes.

Hironori Edamatsu, Senior Assistant Professor
Yoko Yoshikawa, Assistant Professor
Shigeyuki Matsumoto, Designated Assistant Professor
Haruka Taniguchi, Postdoc. Fellow
Ning Ma, Postdoc. Fellow
Chiemi Tsuda, Technical assistant
Farag Maged Ibrahim Ibrahim Abuzeid,
PhD graduate student
Guan Haiqiao, Master's graduate student
Naoto Fujishima, Master's graduate student
Chiho Koyama, Secretary of the Professor
1. Summary
(1) We clarified the molecular basis for the conformational dynamics of the GTP-bound forms of Ras small GTPases (Ras-GTP) by X-ray crystallography and NMR By using a novel strategy based on that, we successfully developed a lead compound of Ras inhibitors having an anti-tumor activity in vivo.
(2) We proved a universal and crucial role of phospholipase Ce (PLCe), an effector of Ras and Rap, in carcinogenesis and inflammation by using PLCe knockout (KO) and transgenic (TG) mice. PLCe seems to augment the expression of proinflammatory cytokines via a novel signaling pathway.
(3) We clarified the essential roles of RA-GEF-1 (Rapgef2) and RA-GEF-2 (Rapgef6), guanine nucleotide exchange factors (GEFs) for Rap1 and Rap2, in angiogenesis, neuronal development, sperm formation, and integrin-mediated lymphocyte adhesion by generating their knockout mice.
(1)Ras inhibitor development using a new strategy based on the conformational dynamics of Ras:
Ras-GTP exhibits dynamic equilibrium between two inter- converting conformations, “inactive” state 1 and “active” state 2. We determined the crystal structures of various Ras mutants representing state 1, state 2, and their inter- mediates to show that hydrogen-bonding interactions of Thr-35 (in switch I) and Gly-60 (in switch II) with the g-phosphate of GTP are abolished in state 1, forming a surface pocket. Assuming that compounds which fit into the pocket could inhibit Ras by stabilizing state 1, we performed in silico screening of 2.5-million virtual compound libraries using computer-docking simulation based on the state 1 structure and obtained hit compounds inhibiting the binding of Ras-GTP to cRaf-1 and the growth of cancer cells carrying the activated ras. Through structural optimization of the hits, we obtained a lead compound showing a potent anti-tumor activity toward human cancers grafted on mice.  
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(2) Universal role of PLCe in carcinogenesis and inflammation:
We discovered PLCe, an effector of Ras/Rap1, and generated PLCe KO mice. They exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis using DMBA as an initiator and phorbor ester TPA as a promoter as well as to the de novo intestinal carcinogenesis in APCMin/+ mice. Considering a close link between tumor promotion and inflammation, we examined the role of PLCe in inflammation and found that PLCe KO mice exhibit substantially attenuated inflammatory responses in various animal models including TPA-induced dermatitis, contact dermatitis, bronchial asthma, and inflammatory bowel disease models. Moreover, TG mice overexpressing PLCe in the skin spontaneously developed chronic skin inflammation resembling human psoriasis. Further, a strong support for its role in human carcinogenesis came from recent GWAS studies (Nat. Genet. 2010), identifying PLCe as a predisposing gene for gastric and esophageal cancers. Studies using cultured keratinocytes suggested that PLCe cooperates with the NF-kB pathway to augment the expression of proinflammatory cytokines. The results introduced PLCe as a candidate molecular target for the development of cancer prophylactic or anti-inflammatory drugs. 
(3) Essential roles of RA-GEF-1 and -2 in cell adhesion, angiogenesis, and neuronal development:
 We discovered a novel class of Rap-GEFs: RA-GEF-1 and -2, whose genes are shown to exhibit copy number variations associated with schizophrenia, and generated their KO mice. RA-GEF-1 KO mice showed embryonic lethality due to a severe defect in blood vessel formation. Cortical neuron-specific RA-GEF-1 KO mice showed hyperproliferation of neuronal progenitor cells and severe neuronal migration defects. RA-GEF-2 KO mice were viable but exhibited a defect in TNF-α-stimulated integrin- mediated adhesion of B-lymphocytes as well as the male sterility due to defective spermatogenesis.