The Journal of Experimental Medicine
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Published online 10 February 2003 doi:10.1084/jem.20021498
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© Rockefeller University Press, 0022-1007/2003/2/503 $5.00
The Journal of Experimental Medicine, Volume 197, Number 4, 503-513

A Mouse with a Loss-of-function Mutation in the c-Cbl TKB Domain Shows Perturbed Thymocyte Signaling without Enhancing the Activity of the ZAP-70 Tyrosine Kinase

Christine B.F. Thien1, Robin M. Scaife1, John M. Papadimitriou1, Maria A. Murphy2, David D.L. Bowtell2 and Wallace Y. Langdon1

1 Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
2 Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 3000, Victoria, Australia

Address correspondence to Wallace Y. Langdon, Dept. of Pathology, University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia. Phone: 61-8-9346-2939; Fax: 61-8-9346-2891; E-mail: wlangdon{at}cyllene.uwa.edu.au

The unique tyrosine kinase binding (TKB) domain of Cbl targets phosphorylated tyrosines on activated protein tyrosine kinases (PTKs); this targeting is considered essential for Cbl proteins to negatively regulate PTKs. Here, a loss-of-function mutation (G304E) in the c-Cbl TKB domain, first identified in Caenorhabditis elegans, was introduced into a mouse and its effects in thymocytes and T cells were studied. In marked contrast to the c-Cbl knockout mouse, we found no evidence of enhanced activity of the ZAP-70 PTK in thymocytes from the TKB domain mutant mouse. This finding contradicts the accepted mechanism of c-Cbl–mediated negative regulation, which requires TKB domain targeting of phosphotyrosine 292 in ZAP-70. However, the TKB domain mutant mouse does show aspects of enhanced signaling that parallel those of the c-Cbl knockout mouse, but these involve the constitutive activation of Rac and not enhanced PTK activity. Furthermore, the enhanced signaling in CD4+CD8+ double positive thymocytes appears to be compensated by the selective down-regulation of CD3 on mature thymocytes and peripheral T cells from both strains of mutant c-Cbl mice.

Key Words: CD3 • CD5 • T cell receptor • SH2 domain • Rac


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