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Identification of novel regulatory mechanisms for for Cdc42 GTPase-activating protein CdGAP/ARHGAP31, a protein involved in development and cancer

by Djoudi Ouadda Ben

Institution: McGill University
Department:
Degree:
Year: 2017
Keywords: Anatomy and Cell Biology
Posted: 2/1/2018 12:00:00 AM
Record ID: 2189654
Full text PDF: http://digitool.library.mcgill.ca/thesisfile146915.pdf


Abstract

Abstract The small Rho GTPase proteins act as molecular switches that regulate diverse cellular processes linked mostly to the actin-cytoskeleton remodeling making them essential regulators of cell adhesion, migration and invasion. Dysregulation of their activities can result in different abnormal phenotypes particularly, tumor progression and metastasis. Hence, regulators of Rho GTPases such as Rho guanine nucleotide exchange factors (RhoGEFs) and Rho GTPase-activating proteins (RhoGAPs), are critical for normal cellular responses and are targets for subversion during oncogenic transformation. CdGAP (Cdc42 GTPase-activating protein) is a member of a well-conserved subfamily of RhoGAP proteins and a negative regulator of the small Rho GTPases, Rac1 and Cdc42. Associated with a rare developmental disorder (AOS, Adams-Oliver Syndrome) and required for a normal angiogenesis, CdGAP plays important roles in the regulation of cell migration and proliferation during early development. In addition, recent findings characterize CdGAP as an essential synergistic component between TGF and HER2/Neu/ErbB-2 signaling pathways which play a positive role in cancer, particularly breast cancer. CdGAP is regulated by lipid binding, protein-protein interactions and phosphorylation, still these mechanisms are not well understood. In this work we first investigate the interaction between CdGAP and its negative regulator, the endocytic protein Intersectin. Using an in vitro approach, we identify a novel, atypical xKx(K/R) (SKSKK) motif in the basic rich (BR) region of CdGAP that directly interacts with the Intersectin-SH3D domain. Moreover, the well-conserved motif is required for the regulation of CdGAP activity following Intersectin binding. Next, we investigate CdGAP phosphorylation and identify two regulatory phospho-serines in the C-terminal (CT) tail, Ser-1093 and Ser-1163, that are phosphorylated by the AGC-kinase family member, RSK1. Finally, we show that 14-3-3 family members bind and regulate both the cellular localization and activity of CdGAP in a Ser-1093 and Ser-1163 phosphorylation-dependent manner. Overall, this work provides two novel CdGAP-regulatory mechanisms that can be applied in therapeutic approaches targeting this RhoGAP, particularly in breast cancers. RsumLes petites protines G de la famille Rho sont des commutateurs molculaires qui contrlent divers procds cellulaires associs notamment, la rgulation du cytosquelette et jouent par consquent, un rle cl dans la rgulation de la motilit cellulaire. La drgulation de leur activit peut entrainer des aberrations se manifestant en particulier, par une progression du cancer et des mtastases. Ainsi, les protines rgulatrices comme les facteurs d'change de nuclotide (RhoGEFs) et les protines activatrices des Rho GTPases (RhoGAPs) sont essentielles pour une signalisation cellulaire normale et sont en gnral, affectes lors des transformations oncogniques. CdGAP (Cdc42-GTPase activating protein) est un membre d'une sous-famille de protinesAdvisors/Committee Members: Nathalie Lamarche (Supervisor).

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