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.
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17 February 2003
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February 10 2003
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. Thien,
Christine B.F. Thien
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
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Robin M. Scaife,
Robin M. Scaife
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
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John M. Papadimitriou,
John M. Papadimitriou
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
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Maria A. Murphy,
Maria A. Murphy
2Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 3000, Victoria, Australia
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David D.L. Bowtell,
David D.L. Bowtell
2Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 3000, Victoria, Australia
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Wallace Y. Langdon
Wallace Y. Langdon
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
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Christine B.F. Thien
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
Robin M. Scaife
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
John M. Papadimitriou
1Department of Pathology, University of Western Australia, Crawley, WA 6009, Australia
Maria A. Murphy
2Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 3000, Victoria, Australia
David D.L. Bowtell
2Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 3000, Victoria, Australia
Wallace Y. Langdon
1Department of Pathology, University of Western Australia, Crawley, WA 6009, 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: [email protected]
*
Abbreviations used in this paper: DP, double positive; ES, embryonic stem; PTK, protein tyrosine kinase; SP, single positive; TKB, tyrosine kinase binding.
Received:
August 23 2002
Revision Received:
December 05 2002
Accepted:
January 06 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 197 (4): 503–513.
Article history
Received:
August 23 2002
Revision Received:
December 05 2002
Accepted:
January 06 2003
Citation
Christine B.F. Thien, Robin M. Scaife, John M. Papadimitriou, Maria A. Murphy, David D.L. Bowtell, Wallace Y. Langdon; 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 . J Exp Med 17 February 2003; 197 (4): 503–513. doi: https://doi.org/10.1084/jem.20021498
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