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Molecular and Cellular Biology, November 2000, p. 8409-8419, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

CD28 and the Tyrosine Kinase Lck Stimulate Mitogen-Activated Protein Kinase Activity in T Cells via Inhibition of the Small G Protein Rap1

Kendall D. Carey,1,2 Tara J. Dillon,1 John M. Schmitt,1,2 Allison M. Baird,1 Amy D. Holdorf,3 David B. Straus,4 Andrey S. Shaw,3 and Philip J. S. Stork1,2,*

Vollum Institute1 and Department of Cell and Developmental Biology,2 Oregon Health Sciences University, Portland, Oregon 97201; Department of Pathology and Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 631103; and Department of Medicine and Pathology, University of Chicago, Chicago, Illinois 606374

Received 3 January 2000/Returned for modification 02 May 2000/Accepted 29 August 2000

Proliferation of T cells via activation of the T-cell receptor (TCR) requires concurrent engagement of accessory costimulatory molecules to achieve full activation. The best-studied costimulatory molecule, CD28, achieves these effects, in part, by augmenting signals from the TCR to the mitogen-activated protein (MAP) kinase cascade. We show here that TCR-mediated stimulation of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited by activation of the Ras antagonist Rap1. CD28 increases ERK signaling by blocking Rap1 action. CD28 inhibits Rap1 activation because it selectively stimulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulate Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our results suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation.

* Corresponding author. Mailing address: Vollum Institute, L-474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098. Phone: (503) 494-4976. Fax: (503) 494-5494. E-mail: stork{at}ohsu.edu.

Molecular and Cellular Biology, November 2000, p. 8409-8419, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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