One of the prominent features of malignant glioma cells is their infiltration into adjacent brain tissues that contributes to tumor recurrence after surgery. Invasion of glioma cells is a multistep process that requires cell adhesion, remodeling of extracellular matrix and cell migration. Our long-term goal is to understand better the mechanisms governing glioma cell migration to facilitate effective treatment of the currently incurable malignant gliomas. The current proposal will be focused on the regulation of glioma cell migration by AGAP2, a GTPase-activating protein that regulates membrane trafficking and is over expressed in malignant gliomas. In our preliminary studies, we find that AGAP2 forms complexes with the focal adhesion kinase (FAK) and the Rho associated kinase ROCK-I. We also find that AGAP2 increases focal adhesion disassembly and glioma cell migration. Based on current knowledge and combined with our findings, we hypothesize that AGAP2 increases malignant glioma cell migration through interaction with FAK and ROCK-I, and through regulation of the trafficking of focal adhesion components and regulators. We will use biochemical and cell biological approaches to test our hypothesis in three specific aims: (1) To characterize the interaction of AGAP2 with FAK and ROCK-I and the regulation of focal adhesion disassembly;(2) To examine the regulation of AGAP2 function in membrane trafficking;and (3) To define the mechanisms by which AGAP2 regulates malignant glioma cell migration. Significance: Completion of the proposed studies will provide the foundation required to fully assess the possibility of targeting AGAP2 or its interaction with regulators of focal adhesions for the treatment of the fatal malignant gliomas.
| Ma, Xiaojie; Espana-Serrano, Laura; Kim, Wan-ju et al. (2014) ?Arrestin1 regulates the guanine nucleotide exchange factor RasGRF2 expression and the small GTPase Rac-mediated formation of membrane protrusion and cell motility. J Biol Chem 289:13638-50 |
| Wu, Yuanjun; Zhao, Yu; Ma, Xiaojie et al. (2013) The Arf GAP AGAP2 interacts with ?-arrestin2 and regulates ?2-adrenergic receptor recycling and ERK activation. Biochem J 452:411-21 |
| Ma, Xiaojie; Zhao, Yu; Daaka, Yehia et al. (2012) Acute activation of ?2-adrenergic receptor regulates focal adhesions through ?Arrestin2- and p115RhoGEF protein-mediated activation of RhoA. J Biol Chem 287:18925-36 |
