title: Digital signaling and hysteresis characterize ras activation in lymphoid cells.
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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jayajit
authors.initials: J
authors.lastname: Das
authors.forename: Mary
authors.initials: M
authors.lastname: Ho
authors.forename: Julie
authors.initials: J
authors.lastname: Zikherman
authors.forename: Christopher
authors.initials: C
authors.lastname: Govern
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D003198:Computer Simulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D018631:ras Proteins