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DETERMINING THE MECHANISM OF NF-kappaB ACTIVATION BY THE SMALL GTPASE RHOB AND THE FUNCTION OF THE RHOB BINDING SCAFFOLD, CCPG1

by
Pedro L. Rodriguez
Biomedical Sciences

B.A., 2003 Rutgers University

Thesis Advisor: Ian Whitehead, Ph.D
Associate Professor

Department of Microbiology and Molecular Genetics

Cancer Center
G-Level Conference Room

Tuesday, January 6, 2009
1:00 p.m.


Abstract

RhoA, RhoB and RhoC make up a subgroup of the Rho GTPase family known as the Rho isoform, which are ~86% homologous and share the function of stimulating stress fibers in cells. Despite this high similarity, RhoB has recenty received the most attention for its unique properties. These include its ability to be early induced by stimuli such as UV radiation, steroids and growth factors; its unique short half-life; its unique cellular localization to endosomal structures and its unique pattern of lipid modification. Whereas RhoA and RhoC are modified by only geranylgeranyl prenyl lipids, RhoB can acquire either geranylgeranyl (RhoB-GG) or farnesyl (RhoB-F) lipids, making it unique to the entire Rho family. Although recent evidence suggests that these isoforms of RhoB localize to separate cellular compartments and that RhoB-GG may have tumor suppressor activity, very few studies have suggested functional relevance for RhoB-F, and none of these have attributed possible functions to particular signaling pathways. The organization of RhoB signaling complexes on scaffolds is also poorly understood and deserves attention. Three studies have been completed, all of which contribute to our understanding of RhoB involvement in NF-B signaling, and regulation by the scaffold protein Ccpg1. These studies identified and characterized (1) specific activation by the RhoB-F variant of NF-B signaling in various cell types; (2) a ROCK-dependent mechanism for RhoB-mediated NF-B signaling; (3) inhibition of RhoB as well as RhoA and RhoC activity by the novel scaffold Ccpg1. In the second study, factors that activate NF-B through RhoB were also identified. This involved signals emanating from the endosomal compartment and implicate RhoBs role as a sensor for a novel endosome-derived stress pathway that arrises due to aberrant regulation of endosomal sorting by factors found on the late endosome and multi-vesicular body. The third study also included a functional analysis of the interaction between Ccpg1 and Src. These studies did not support a role for Src regulation by Ccpg1 in one cell type, but hint at precise Src pathway regulation in other cells. This suggests that the properties of the scaffold Ccpg1 could be context and cell type specific. Collectively, these studies reveal new upstream and downstream contributors to RhoB signaling and have implications for RhoBs involvement in cellular transformation.


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