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| Subject Categories: Immunology |
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| The EMBO Journal
(2005) 24, 3807–3819, doi:10.1038/sj.emboj.7600841 Published online 6 October 2005 |
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| Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion |
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| Christine B F Thien1, Frøydis D Blystad1, 4, Yifan Zhan2, Andrew M Lew2, Valentina Voigt3, Christopher E Andoniou3 and Wallace Y Langdon1 |
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1 School of Surgery and Pathology, University of Western Australia, Crawley, Australia 2 The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Melbourne, Australia 3 Centre for Experimental Immunology, The Lions Eye Institute, Nedlands, Australia To whom correspondence should be addressed Wallace Y Langdon, School of Surgery and Pathology, University of Western Australia, Crawley, WA 6009, Australia. Tel.: +61 8 9346 2939; Fax: +61 8 9346 2891; E-mail: wlangdon@cyllene.uwa.edu.au 4 Present address: Institute of Pathology, University of Oslo, Rikshospitalet, Norway Received 19 July 2005; Accepted 19 September 2005; Published online 6 October 2005. |
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| Abstract |
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| Signaling from the T-cell receptor (TCR) in thymocytes is negatively regulated by the RING finger-type ubiquitin ligase c-Cbl. To further investigate this regulation, we generated mice with a loss-of-function mutation in the c-Cbl RING finger domain. These mice exhibit complete thymic deletion by young adulthood, which is not caused by a developmental block, lack of progenitors or peripheral T-cell activation. Rather, this phenotype correlates with greatly increased expression of the CD5 and CD69 activation markers and increased sensitivity to anti-CD3-induced cell death. Thymic loss contrasts the normal fate of the c-Cbl-/- thymus, even though thymocytes from both mutant mice show equivalent enhancement in proximal TCR signaling, Erk activation and calcium mobilization. Remarkably, only the RING finger mutant thymocytes show prominent TCR-directed activation of Akt. We show that the mutant c-Cbl protein itself is essential for activating this pathway by recruiting the p85 regulatory subunit of PI 3-kinase. This study provides a unique model for analyzing high-intensity TCR signals that cause thymocyte deletion and highlights multiple roles of c-Cbl in regulating this process. |
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| Keywords: Akt, apoptosis, Cbl, CD3, thymus |
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