Activation of the Ras-related GTPase Rap1 by thymocyte TCR engagement and during selection.

Signals mediated by activation of the small GTPase Ras play an essential role both in thymocyte development and in TCR-mediated activation of mature T cells. Given the critical requirement of Ras signaling pathways in thymocyte development, and recent indications that Rap1 may negatively regulate Ras-dependent signaling pathways, we examined the ...
possible involvement of Rap1 in thymocyte TCR signaling. We find that Rap1 and proposed regulators of Rap1 (the proto-oncogene product Cbl, Crk family adaptor proteins, and the Rap1 guanine nucleotide exchange factor C3G) are expressed at equivalent levels in both double-negative and double-positive murine thymocytes. Rap1 was transiently activated following TCR stimulation of both total thymocytes and purified double-positive thymocytes, and this activation correlated with tyrosine phosphorylation of Cbl and Cbl association with CrkL. TCR-dependent Rap1 activation was enhanced by co-stimulation through CD28 and could be mimicked by treatment of thymocytes with phorbol ester and calcium. In contrast to mature peripheral T lymphocytes, Rap1 stimulation by CD3 ligation in thymocytes did not require intracellular calcium mobilization. Intriguingly, we found a clear elevation of activated Rap1 in thymocytes undergoing positive selection, suggesting a functional role for Rap1 in thymocyte development and selection.
Mesh Terms:
Animals, Antigens, CD28, Antigens, CD3, Calcium Signaling, Clonal Deletion, Enzyme Activation, Humans, Jurkat Cells, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-crk, Receptors, Antigen, T-Cell, Signal Transduction, Specific Pathogen-Free Organisms, T-Lymphocytes, Ubiquitin-Protein Ligases, rap1 GTP-Binding Proteins, ras Proteins
Eur. J. Immunol.
Date: Oct. 01, 2000
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