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Molecular and Cellular Biology, April 2007, p. 2732-2745, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01882-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Unusual Interplay of Two Types of Ras Activators, RasGRP and SOS, Establishes Sensitive and Robust Ras Activation in Lymphocytes{triangledown}

Jeroen P. Roose,1,{dagger} Marianne Mollenauer,1 Mary Ho,1,{dagger} Tomohiro Kurosaki,3 and Arthur Weiss1,2*

Department of Medicine and Department of Microbiology and Immunology, Howard Hughes Medical Institute,1 Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, California 94143-0795,2 Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokahama, Kanagawa 230-005, Japan3

Received 5 October 2006/ Returned for modification 4 November 2006/ Accepted 15 January 2007

Ras activation is crucial for lymphocyte development and effector function. Both T and B lymphocytes contain two types of Ras activators: ubiquitously expressed SOS and specifically expressed Ras guanyl nucleotide-releasing protein (RasGRP). The need for two activators is enigmatic since both are activated following antigen receptor stimulation. In addition, RasGRP1 appears to be dominant over SOS in an unknown manner. The crystal structure of SOS provides a clue: an unusual allosteric Ras-GTP binding pocket. Here, we demonstrate that RasGRP orchestrates Ras signaling in two ways: (i) by activating Ras directly and (ii) by facilitating priming of SOS with RasGTP that binds the allosteric pocket. Priming enhances SOS' in vivo activity and creates a positive RasGTP-SOS feedback loop that functions as a rheostat for Ras activity. Without RasGRP1, initiation of this loop is impaired because SOS' catalyst is its own product (RasGTP)—hence the dominance of RasGRP1. Introduction of an active Ras-like molecule (RasV12C40) in T- and B-cell lines can substitute for RasGRP function and enhance SOS' activity via its allosteric pocket. The unusual RasGRP-SOS interplay results in sensitive and robust Ras activation that cannot be achieved with either activator alone. We hypothesize that this mechanism enables lymphocytes to maximally respond to physiologically low levels of stimulation.

* Corresponding author. Mailing address: UCSF, 513 Parnassus Ave., Room S-1032C, San Francisco, CA 94143-0795. Phone: (415) 476-8983. Fax: (415) 502-5081. E-mail: aweiss{at}medicine.ucsf.edu.

{triangledown} Published ahead of print on 5 February 2007.

{dagger} Present address: UCSF, Department of Anatomy, 513 Parnassus Ave., Room HSW-1326, San Francisco, CA 94143-0452.

Molecular and Cellular Biology, April 2007, p. 2732-2745, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01882-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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