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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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.
Bibliographical noteFunding Information:
We thank Dr. Kurosaki for DT40 lines and Dr. Dafna Bar-sagi for the H-RasG59E38 plasmid. We are grateful to Dr. DeFranco and members of the Weiss, Chakraborty, and Roose labs for critical reading of the manuscript. We apologize to colleagues we could not cite due to space constraints. Financial support: NIH Director's Pioneer Award and 1PO1/AI071195/01 (A.K.C.), the Howard Hughes Medical Institute as well as the Rosalind Russell Medical Research Center for Arthritis (A.W.), and the NCI (K01CA113367), Arthritis Foundation, and Sandler Foundation (J.P.R.).