Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells

Jayajit Das; Mary Ho; Julie Zikherman; Christopher Govern; Ming Yang; Arthur Weiss; Arup K. Chakraborty; Jeroen P. Roose

doi:10.1016/j.cell.2008.11.051

Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells

Jayajit Das
, Mary Ho
, Julie Zikherman
, Christopher Govern
, Ming Yang
, Arthur Weiss
, Arup K. Chakraborty
, Jeroen P. Roose

Research output: Contribution to journal › Article › peer-review

338 Scopus citations

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leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit "memory" of past encounters with antigen.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

Original language	English
Pages (from-to)	337-351
Number of pages	15
Journal	Cell
Volume	136
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2008.11.051
State	Published - 23 Jan 2009
Externally published	Yes

Bibliographical note

Funding 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.).

Funding

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.).

Funders	Funder number
Rosalind Russell Medical Research Center for Arthritis
National Institutes of Health
Howard Hughes Medical Institute
National Cancer Institute	K01CA113367
National Institute of Allergy and Infectious Diseases	P01AI071195
Arthritis Foundation
Sandler Foundation

Keywords

MOLIMMUNO
SIGNALING
SYSBIO

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10.1016/j.cell.2008.11.051

Cite this

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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.",

keywords = "MOLIMMUNO, SIGNALING, SYSBIO",

author = "Jayajit Das and Mary Ho and Julie Zikherman and Christopher Govern and Ming Yang and Arthur Weiss and Chakraborty, \{Arup K.\} and Roose, \{Jeroen P.\}",

note = "Funding 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.). ",

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AU - Das, Jayajit

AU - Ho, Mary

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AU - Govern, Christopher

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AU - Weiss, Arthur

AU - Chakraborty, Arup K.

AU - Roose, Jeroen P.

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PY - 2009/1/23

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N2 - 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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Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells

Abstract

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Keywords

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