Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Jan 27

PMID 19167334

Citations 226

Authors

Jayajit Das

Mary Ho

Julie Zikherman

Christopher Govern

Ming Yang

Arthur Weiss

Arup K Chakraborty

Jeroen P Roose

Affiliations

Soon will be listed here.

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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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.

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