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Pascale Charest

Honors

• Fonds de la Recherche en Sante du Quebec post-doctoral fellow, 2005-2008
• Heart and Stroke Foundation of Canada graduate fellow, 2001-2004
• Fonds de la Recherche en Sante du Quebec graduate fellow, 2001-2003
• Canadian Hypertension Society graduate fellow, 1999-2000

Education and Appointments

• B.Sc. 1998, Universite de Sherbrooke
  
• M.Sc. 2000, Universite de Montreal
  
• Ph.D. 2005, Universite de Montreal
  
• Postdoctoral fellow 2005-2010, University of California, San Diego
  
• Assist. Project Scientist 2010-2011, University of California, San Diego
  

Research Interests

• Biochemistry
  
• "Metabolism, Signaling, and Regulation"
  
• Bioanalytical
  
• Chemical Biology
  

Research Summary

Our research focuses on the signal transduction pathways and molecular mechanisms controlling directed cell migration, or chemotaxis, in eukaryotic cells. Chemotaxis is central to many biological processes, including the embryonic development, wound healing, the migration of white blood cells (leukocytes) to sites of inflammation or bacterial infection, as well as the metastasis of cancer cells. Cells can sense chemical gradients that are as shallow as a 2% difference in concentration across the cell, and migrate towards the source of the signal, the chemoattractant. This is achieved through an intricate network of intracellular signaling pathways that are triggered by the chemoattractant signal. These pathways ultimately translate the detected chemoattractant gradient into changes in the cytoskeleton that lead to cell polarization and forward movement. In addition, many cells such as leukocytes and Dictyostelium, transmit the chemoattractant signal to other cells by themselves secreting chemoattractants, which increases the number of cells reaching the chemoattractant source.

To investigate the mechanisms of signal transduction underlying chemotaxis, we are using Dictyostelium discoideum, a model genetic system. Cell motility and chemotaxis of Dictyostelium cells is very similar to that of leukocytes and cancer cells, using the same underlying cellular processes as these higher eukaryotic cells. Dictyostelium is amenable to cell biological, biochemical, and genetic approaches that are unavailable in more complex systems. We take a Systems Biology approach, combining molecular genetic, proteomics and phosphoproteomics, to identify new signaling proteins and pathways involved in the control of chemotaxis. We couple this approach with live cell imaging to understand the spatiotemporal dynamics of the signaling events, and with biochemical and biophysical analyses (including Bioluminescence Resonnance Energy Transfer; BRET) to understand how proteins interact and function within the signaling network.

Selected Publications

K. Takeda, D. Shao, M. Adler, P.G. Charest, W.F. Loomis, H. Levine, A. Groisman, W.J. Rappel, and R.A. Firtel. Incoherent feedforward control governs adaptation of activated Ras in eukaryotic chemotaxis pathway. Sci. Signal. 5, ra2 (2012).

I. Hecht, M.L. Skoge, P.G. Charest, E. Ben-Jacob, R.A. Firtel, W.F. Loomis, H. Levine, and W.J. Rappel. Activated membrane patches guide chemotactic cell motility. PLoS Comput. Biol. 7(6):e1002044 (2011).

P.G. Charest, Z. Shen, A. Lakoduk, A.T. Sasaki, S.P. Briggs and R.A. Firtel. A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration. Dev. Cell. 18:737-49 (2010).

S. Zhang*, P.G. Charest*, and R.A. Firtel. Spatio-temporal Regulation of Ras Activity Provides Directional Sensing. Curr. Biol. 18(20):1587-93 (2008). * Equal authorship.

A.T. Sasaki, C. Janetopoulos, S. Lee, P.G. Charest, K. Takeda, L.W. Sunddheimer, R. Meili, P.N. Devreotes and R.A. Firtel. G Protein-Independent Ras/PI3K/F-Actin Circuit Regulates Basic Cell Motility. J. Cell. Biol. 178(2):185-91 (2007).

P.G. Charest, G. Oligny-Longpre, H. Bonin, M. Azzi and M. Bouvier. The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling. Cell. Signal. 19(1):32-41 (2007).

P.G. Charest, S. Terrillon and M. Bouvier. Monitoring agonist-promoted conformational changes of beta-arrestin in living cells by intramolecular BRET. EMBO rep. 6(4): 334-40 (2005).

P.G. Charest and M.Bouvier. Palmitoylation of the V2 vasopressin receptor carboxyl tail facilitates beta-arrestin recruitment leading to efficient receptor endocytosis and ERK1/2 activation. J. Biol. Chem. 278(42):41541-51 (2003).