Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes
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Chakraborty_Molecular origin.pdf
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Author(s)
Das, Jayajit
Zikherman, Julie
Yang, Ming
Govern, Christopher C.
Ho, Mary
Weiss, Arthur
Roose, Jeroen
Chakraborty, Arup K
Date Issued
April 2009
Journal
Science Signaling
Publisher
American Association for the Advancement of Science
Citation
Chakraborty, A. K., J. Das, J. Zikherman, M. Yang, C. C. Govern, M. Ho, A. Weiss, and J. Roose. “Molecular Origin and Functional Consequences of Digital Signaling and Hysteresis During Ras Activation in Lymphocytes.” Science Signaling 2, no. 66 (April 14, 2009): pt2-pt2.
Version
Author's final manuscript
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.
Description
available in PMC 2009 October 1; A presentation from the EMBO workshop "Visualizing Immune System Complexity," Centre d'Immunologie Marseille-Luminy, Marseille, France, 15 to 17 January 2009.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1126/scisignal.266pt2
