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Molecular and Cellular Biology, June 2005, p. 4426-4441, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4426-4441.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Diacylglycerol-Protein Kinase C-RasGRP1 Pathway Directs Ras Activation upon Antigen Receptor Stimulation of T Cells

Jeroen P. Roose,1 Marianne Mollenauer,1 Vikas A. Gupta,1 James Stone,3 and Arthur Weiss1,2*

Departments of Medicine, Microbiology, and Immunology and Howard Hughes Medical Institute,1 Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, California 94143,2 Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2G7, Canada3

Received 12 October 2004/ Returned for modification 10 November 2004/ Accepted 1 March 2005

Ras GTPases are on/off switches regulating numerous cellular responses by signaling to various effector molecules. In T lymphocytes, Ras can be activated by two Ras exchange factors, SOS and RasGRP1, which are recruited through the adapters Grb2 and LAT and via the second-messenger diacylglycerol (DAG), respectively. Mitogen-activated protein (MAP) kinase phosphorylation patterns induced by active Ras can vary and contribute to distinct cellular responses. The different consequences of Ras activation by either guanine exchange factor are unknown. DAG also recruits and activates the kinase protein kinase C{theta} (PKC{theta}) turning on the Erk MAP kinase pathway, but the biochemical mechanism responsible is unclear. We generated T-cell clones deficient in phorbol myristate acetate (a surrogate for DAG)-induced Ras activation. Analysis of a RasGRP1-deficient Jurkat T-cell clone and RasGRP1 RNA interference in wild-type cells revealed that RasGRP1 is required for optimal, antigen receptor-triggered Ras-Erk activation. RasGRP1 relies on its DAG-binding domain to selectively activate Erk kinases. Activation of Erk correlates with the phosphorylation of threonine residue 184 in RasGRP1. This phosphorylation event requires the activities of novel PKC kinases. Conversely, active PKC{theta} depends on RasGRP1 sufficiency to effectively trigger downstream events. Last, DAG-PKC-RasGRP1-driven Ras-Erk activation in T cells is a unique signaling event, not simply compensated for by SOS activity.

* Corresponding author. Mailing address: Departments of Medicine, Microbiology, and Immunology, UCSF, 533 Parnassus Avenue, Room U-330, San Francisco, CA 94143. Phone: (415) 476-1291. Fax: (415) 502-5081. E-mail: aweiss{at}medicine.ucsf.edu.

Molecular and Cellular Biology, June 2005, p. 4426-4441, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4426-4441.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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