Research Papers:

CdGAP/ARHGAP31 is regulated by RSK phosphorylation and binding to 14-3-3β adaptor protein

Ali Ben Djoudi Ouadda _, Yi He, Viviane Calabrese, Hidetaka Ishii, Rony Chidiac, Jean-Philippe Gratton, Philippe P. Roux and Nathalie Lamarche-Vane

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Oncotarget. 2018; 9:11646-11664. https://doi.org/10.18632/oncotarget.24126

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Ali Ben Djoudi Ouadda1,2, Yi He1,2, Viviane Calabrese3, Hidetaka Ishii1,2, Rony Chidiac4, Jean-Philippe Gratton4, Philippe P. Roux3 and Nathalie Lamarche-Vane1,2

1Cancer Research Program, Research Institute of the MUHC, Montreal, Quebec, H4A 3J1, Canada

2McGill University, Department of Anatomy and Cell Biology, Montreal, Quebec, H3A 2B2, Canada

3Institute for Research in Immunology and Cancer (IRIC), Montreal, Quebec, H3T 1J4, Canada

4Department of Pharmacology, Faculty of Medicine, Université de Montréal, Department of pharmacology, Montreal, Quebec, H3T 1J4, Canada

Correspondence to:

Nathalie Lamarche-Vane, email: [email protected]

Keywords: RhoGAPs; RSK; 14-3-3; phosphorylation; cytoskeleton

Received: June 29, 2017     Accepted: December 03, 2017     Published: January 10, 2018


Cdc42 GTPase-activating protein (CdGAP, also named ARHGAP31) is a negative regulator of the GTPases Rac1 and Cdc42. Associated with the rare developmental disorder Adams-Oliver Syndrome (AOS), CdGAP is critical for embryonic vascular development and VEGF-mediated angiogenesis. Moreover, CdGAP is an essential component in the synergistic interaction between TGFβ and ErbB-2 signaling pathways during breast cancer cell migration and invasion, and is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer. CdGAP is highly phosphorylated on serine and threonine residues in response to growth factors and is a substrate of ERK1/2 and GSK-3. Here, we identified Ser1093 and Ser1163 in the C-terminal region of CdGAP, which are phosphorylated by RSK in response to phorbol ester. These phospho-residues create docking sites for binding to 14-3-3 adaptor proteins. The interaction between CdGAP and 14-3-3 proteins inhibits the GAP activity of CdGAP and sequesters CdGAP into the cytoplasm. Consequently, the nucleocytoplasmic shuttling of CdGAP is inhibited and CdGAP-induced cell rounding is abolished. In addition, 14-3-3β inhibits the ability of CdGAP to repress the E-cadherin promoter and to induce cell migration. Finally, we show that 14-3-3β is unable to regulate the activity and subcellular localization of the AOS-related mutant proteins lacking these phospho-residues. Altogether, we provide a novel mechanism of regulation of CdGAP activity and localization, which impacts directly on a better understanding of the role of CdGAP as a promoter of breast cancer and in the molecular causes of AOS.

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