Role of the polarity RhoGEF PLEKHG5 on brain tumor dispersal

DESCRIPTION (provided by applicant): A major issue in the management of brain tumors is their aggressive growth and invasion into surrounding normal brain tissue. Unfortunately, our understanding of the mechanisms that underlie the aggressive behavior of these tumors is very limited. Recent evidence indicates that the invasiveness of solid tumors involves signaling events downstream of Rho GTPases. The Rho family of small GTPases in general and RhoA in particular, are critical regulators of cell adhesion, cell polarity, directed cell migration and asymmetric cell division, through their effects on the actin cytoskeleton and microtubules. Our basic research findings on the mechanics of cell adhesion and migration have identified the Rho guanine exchange factor (GEF) PLEKHG5 as important in promoting directed cell migration, via its interaction with a complex of polarity proteins, including MUPP1, PATJ, PALS1, and LIN7, and activation of RhoA signaling. Interestingly, our preliminary data indicate that PLEKHG5 and its cell polarity partner MUPP1 are highly expressed in human gliomas. Preliminary experiments support the involvement of PLEKHG5 in the increased migration of glioma cells in vitro. Therefore, we postulate that that recruitment to and activation of PLEKHG5 at the leading edges of migrating glioma cells specifically regulates RhoA activity to promote the directional migration and invasiveness of glioma cells. Our main objectives are to define the involvement of PLEKHG5 in glioma cell migration and invasion, and to identify the mechanisms that regulate the sub-cellular localization of PLEKHG5 and its effects on directed cell migration. To achieve these objectives we propose to: 1. Assess whether PLEKHG5-mediated RhoA activation promotes the directed migration and increased invasiveness of glioma cells. 2. Determine the role of interacting polarity proteins, PLEKHG5 phosphorylation, and downstream effectors on PLEKHG5 activity, sub-cellular localization and directed cell migration, PUBLIC HEALTH RELEVANCE: Malignant gliomas grow aggressively, and their spread into surrounding normal brain tissue is a major factor in their poor clinical outcome, underscoring the need for new insights into the etiology and therapeutic intervention of these tumors. Our research findings have identified PLEKHG5 as an important player in inducing cell polarization and cell migration. In this study, we will define the role of PLEKHG5 in glioma biology, and identify mechanisms by which it promotes the aggressive invasive behavior of human gliomas.