the mechanism of RH-RhoGEF activation by G12/13

Research Project

Project/Area Number	24390060
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Partial Multi-year Fund
Section	一般
Research Field	General pharmacology
Research Institution	The University of Tokyo
Principal Investigator	KOZASA Tohru 東京大学, 先端科学技術研究センター, 特任教授 (70202059)
Co-Investigator(Kenkyū-buntansha)	SUZUKI Nobuchika 東京大学, 先端科学技術研究センター, 特任助教 (90247007)
Project Period (FY)	2012-04-01 – 2015-03-31
Project Status	Completed (Fiscal Year 2014)
Budget Amount *help	¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000) Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000) Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000) Fiscal Year 2012: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Keywords	G蛋白質 / 癌細胞 / シグナル伝達 / Rho
Outline of Final Research Achievements	RH-RhoGEFs (Rho guanine nucleotide exchange factor containing a regulator of G protein signaling homology domain) including PDZ-RhoGEF, p115RhoGEF, and leukemia-associated RhoGEF potentiated by direct binding with activated heterotrimeric G proteins G12/13 have been thought to play a pivotal role in malignancy progression through the small GTPase RhoA activation. Here we describe a key mechanism for GRPR-regulated colon cancer cell migration through the Gα13~PDZ-RhoGEF~RhoA~ROCK pathway. We have also found that GEF-independent function of p115RhoGEF, one of RH-RhoGEFs promotes differentiation of human leukemic cells. In addition, we successfully solved the crystal structure of Gα12 and the RH domain of p115RhoGEF. We are solving the mechanism by which p115RhoGEF is activated by Gα13, but not Gα12.