Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells
Name
Das-2009-Digital Signaling an.pdf
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2.6 MB
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Author(s)
Das, Jayajit
Ho, Mary
Zikherman, Julie
Govern, Christopher C.
Yang, Ming
Weiss, Arthur
Chakraborty, Arup K.
Roose, Jeroen P.
Date Issued
January 2009
Journal
Cell
Publisher
Elsevier
Citation
Das, Jayajit, Mary Ho, Julie Zikherman, Christopher Govern, Ming Yang, Arthur Weiss, Arup K. Chakraborty, and Jeroen P. Roose. “Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells.” Cell 136, no. 2 (January 2009): 337–351. © 2009 Elsevier Inc.
Version
Final published version
Abstract
Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, RasGRP and SOS, catalyze Ras activation in lymphocytes. Binding of active Ras to SOS' allosteric pocket markedly increases SOS' activity establishing a positive feedback loop for SOS-mediated Ras activation. Integrating in silico and in vitro studies, we demonstrate that digital signaling in lymphocytes (cells are “on” or “off”) is predicated upon feedback regulation of SOS. SOS' feedback loop leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit “memory” of past encounters with antigen. Ras activation via RasGRP alone is analog (graded increase in amplitude with stimulus). We describe how complementary analog (RasGRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output. Numerous predictions regarding the impact of our findings on lymphocyte function and development are noted.
MIT Department
Institute for Medical Engineering and 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/10.1016/j.cell.2008.11.051
