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Titolo:
T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase
Autore:
Magnan, A; Di Bartolo, V; Mura, AM; Boyer, C; Richelme, M; Lin, YL; Roure, A; Gillet, A; Arrieumerlou, C; Acuto, O; Malissen, B; Malissen, M;
Indirizzi:
Univ Med, Ctr Immunol Marseille Luminy, CNRS, INSERM, F-43288 Marseille 9,France Univ Med Marseille France 9 ny, CNRS, INSERM, F-43288 Marseille 9,France Inst Pasteur, Mol Immunol Unit, F-75724 Paris, France Inst Pasteur ParisFrance F-75724 ol Immunol Unit, F-75724 Paris, France Inst Cochin Genet Mol, Lab Immunopharmacol, CNRS, UPR 415, F-75014 Paris, France Inst Cochin Genet Mol Paris France F-75014 PR 415, F-75014 Paris, France
Titolo Testata:
JOURNAL OF EXPERIMENTAL MEDICINE
fascicolo: 4, volume: 194, anno: 2001,
pagine: 491 - 505
SICI:
0022-1007(20010820)194:4<491:TCDATC>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHOSPHOTYROSINE-BINDING DOMAIN; MEDIATED SIGNAL-TRANSDUCTION; ANTIGEN RECEPTOR FUNCTION; SRC HOMOLOGY-2 DOMAIN; PROTOONCOGENE C-CBL; NEGATIVE REGULATION; POSITIVE SELECTION; THYMOCYTE DEVELOPMENT; PHOSPHORYLATION SITE; TRANSGENIC MICE;
Keywords:
gene knockin; T cell antigen receptor; Vav1; Cbl; signal transduction;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
70
Recensione:
Indirizzi per estratti:
Indirizzo: Malissen, M Univ Med, Ctr Immunol Marseille Luminy, CNRS, INSERM, Case 906,Parc Sci Luminy, F-43288 Marseille 9, France Univ Med Case 906,Parc Sci Luminy Marseille France 9 , France
Citazione:
A. Magnan et al., "T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase", J EXP MED, 194(4), 2001, pp. 491-505

Abstract

After stimulation of the T cell receptor (TCR), the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP-70 become phosphorylated and plausibly function as docking sites for Cbl and Vav1, respectively. The two latter proteins have been suggested to serve as substrates for ZAP-70 and to fine-tune its function. To address the role of these residues in T cell development and in the function of primary T cells, we have generated mice that express ZAP-70 molecules with Tyr to Phe substitution atposition 292 (Y292F) or 315 (Y315F). When analyzed in a sensitized TCR transgenic background, the ZAP-70 Y315F mutation reduced the rate of positive selection and delayed the occurrence of negative selection. Furthermore, this mutation unexpectedly affected the constitutive levels of the CD3-zeta p21 phosphoisoform. Conversely, the ZAP-70 Y292F mutation upregulated proximal events in TCR signaling and allowed more T cells to produce interleukin 2 and interferon gamma in response to a given dose of antigen. The observation that ZAP-70 Y292F T cells have a slower rate of ligand-induced TCP, downmodulation suggests that Y292 is likely involved in regulating the duration activated TCR reside at the cell surface. Furthermore, we showed that Y292 and Y315 are dispensable for the TCR-induced tyrosine phosphorylation of Cbl and Vav1, respectively. Therefore, other molecules present in the TCR signaling cassette act as additional adaptors for Cbl and Vav1. The present in vivo analyses extend previous data based on transformed T cell lines andsuggest that residue Y292 plays a role in attenuation of TCR signaling, whereas residue Y315 enhances ZAP-70 function.

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Documento generato il 01/10/20 alle ore 16:20:20