the mechanism of RH-RhoGEF activation by G12/13

2014 Fiscal Year Final Research Report

• 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
• Keywords: G蛋白質 / 癌細胞

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.

Free Research Field

生化学