Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells
Author(s)Das, Jayajit; Ho, Mary; Zikherman, Julie; Govern, Christopher C.; Yang, Ming; Weiss, Arthur; Chakraborty, Arup K.; Roose, Jeroen P.; ... Show more Show less
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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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit “memory” of past encounters with antigen.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.
DepartmentInstitute 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
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.
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