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Molecular and Cellular Biology, December 2000, p. 8740-8747, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Combinatorial Effect of T-Cell Receptor Ligation and CD45 Isoform Expression on the Signaling Contribution of the Small GTPases Ras and Rap1

Jan Czyzyk,1,2 David Leitenberg,1,3 Tom Taylor,1 and Kim Bottomly1,*

Section of Immunobiology,1 Department of Pathology,2 and Department of Laboratory Medicine,3 Yale University School of Medicine, New Haven, Connecticut 06510

Received 21 March 2000/Returned for modification 24 April 2000/Accepted 8 September 2000

By using ligands with various affinities for the T-cell receptor (TCR) and by altering the contribution of the CD45 tyrosine phosphatase, the effects of the potency of TCR-induced signals on the function of small GTPases Ras and Rap1 were studied. T cells expressing low-molecular-weight CD45 isoforms (e.g., CD45RO) exhibited the strongest activation of the Ras-dependent Elk-1 transcription factor and the highest sensitivity to the inhibitory action of dominant negative mutant Ras compared to T cells expressing high-molecular-weight CD45 isoforms (ABC). Moreover, stimulation of CD45RO+, but not CD45ABC+, T cells with a high-affinity TCR ligand induced suboptimal Elk-1 activation compared with the stimulation induced by an intermediate-affinity TCR-ligand interaction. This observation suggested that the Ras-dependent signaling pathway is safeguarded in CD45RO+ expressors by a negative regulatory mechanism(s) which prohibits maximal activation of the Ras-dependent signaling events following high-avidity TCR-ligand engagement. Interestingly, the biochemical activity of another small GTPase, the Ras-like protein Rap1, which has been implicated in the functional suppression of Ras signaling, was inversely correlated with the extent of Elk-1 activation induced by different-affinity TCR ligands. Consistently, overexpression of putative Rap dominant negative mutant RapN17 or the physiologic inhibitor of Rap1, the Rap GTPase-activating protein RapGAP, augmented the Elk-1 response in CD45RO+ T cells. This is in contrast to the suppressive effect of RapN17 and RapGAP on CD45ABC+ T cells, underscoring the possibility that Rap1 can act as either a repressor or a potentiator of Ras effector signals, depending on CD45 isoform expression. These observations suggest that cells expressing distinct isoforms of CD45 employ different signal transduction schemes to optimize Ras-mediated signal transduction in activated T lymphocytes.

* Corresponding author. Mailing address: Section of Immunobiology, Yale University School of Medicine, 310 Cedar St.-LH 408, New Haven, CT 06510. Phone: (203) 785-5391. Fax: (203) 737-1764. E-mail: kim.bottomly{at}yale.edu.

Molecular and Cellular Biology, December 2000, p. 8740-8747, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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