TY - JOUR
T1 - Molecular origin and functional consequences of digital signaling and hysteresis during ras activation in lymphocytes
AU - Chakraborty, Arup K.
AU - Das, Jayajit
AU - Zikherman, Julie
AU - Yang, Ming
AU - Govern, Christopher C.
AU - Ho, Mary
AU - Weiss, Arthur
AU - Roose, Jeroen
PY - 2009/4/14
Y1 - 2009/4/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=70349235821&partnerID=8YFLogxK
U2 - 10.1126/scisignal.266pt2
DO - 10.1126/scisignal.266pt2
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C2 - 19366993
AN - SCOPUS:70349235821
SN - 1945-0877
VL - 2
SP - pt2
JO - Science Signaling
JF - Science Signaling
IS - 66
ER -