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Sci. Signal., 14 April 2009
Vol. 2, Issue 66, p. pt2
[DOI: 10.1126/scisignal.266pt2]

PRESENTATIONS

Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes

Arup K. Chakraborty1,2,3{ddagger}, Jayajit Das1,*, Julie Zikherman4, Ming Yang1, Christopher C. Govern1, Mary Ho5,{dagger}, Arthur Weiss4,6, and Jeroen Roose5

1 Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
2 Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
3 Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
4 Division of Rheumatology, Department of Medicine, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
5 Department of Anatomy, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
6 Howard Hughes Medical Institute, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
* Present address: Battelle Center for Mathematical Medicine, Nationwide Children's Hospital and Department of Pediatrics, and Biophysics Graduate Program, Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
{dagger} Present address: Graduate School of Physical Therapy, Samuel Merritt University, 450 30th Street, Suite 2800, Oakland, CA 94609, USA.

A presentation from the EMBO workshop "Visualizing Immune System Complexity," Centre d'Immunologie Marseille-Luminy, Marseille, France, 15 to 17 January 2009.

Abstract: Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, Ras-GRP and SOS (Ras–guanine nucleotide–releasing protein and Son of Sevenless, respectively), catalyze Ras activation in lymphocytes. Binding of active Ras to the allosteric pocket of SOS markedly increases the activity of SOS. Thus, there is a positive feedback loop regulating SOS. Combining in silico and in vitro studies, we demonstrate that "digital" signaling in lymphocytes (cells are "on" or "off") is predicated on this allosteric regulation of SOS. The SOS feedback loop leads to hysteresis in the dose-response curve, which may enable T cells to exhibit "memory" of past encounters with antigen. Ras activation by Ras-GRP alone is "analog" (a graded increase in activation in response to an increase in the amplitude of the stimulus). We describe how the complementary analog (Ras-GRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output and make predictions regarding the importance of digital signaling in lymphocyte function and development.

{ddagger} Presenter and corresponding author. E-mail, arupc{at}mit.edu

Citation: A. K. Chakraborty, J. Das, J. Zikherman, M. Yang, C. C. Govern, M. Ho, A. Weiss, J. Roose, Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes. Sci. Signal. 2, pt2 (2009).

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