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Titolo:
Specific subdomains of Vav differentially affect T cell and NK cell activation
Autore:
Billadeau, DD; Mackie, SM; Schoon, RA; Leibson, PJ;
Indirizzi:
Mayo Clin, Dept Immunol, Mayo Grad & Med Sch, Rochester, MN 55905 USA MayoClin Rochester MN USA 55905 Grad & Med Sch, Rochester, MN 55905 USA
Titolo Testata:
JOURNAL OF IMMUNOLOGY
fascicolo: 8, volume: 164, anno: 2000,
pagine: 3971 - 3981
SICI:
0022-1767(20000415)164:8<3971:SSOVDA>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
NATURAL-KILLER-CELLS; PHOSPHATIDYLINOSITOL 4-PHOSPHATE 5-KINASE; TRANSCRIPTION FACTOR NFAT1; GTP EXCHANGE FACTOR; FC-GAMMA-RIIIA; SIGNAL-TRANSDUCTION; PROTOONCOGENE PRODUCT; NUCLEAR FACTOR; RHO-FAMILY; CYTOSKELETAL REORGANIZATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
75
Recensione:
Indirizzi per estratti:
Indirizzo: Leibson, PJ Mayo Clin, Dept Immunol, Mayo Grad & Med Sch, 200 1st St SW, Rochester, MN55905 USA Mayo Clin 200 1st St SW Rochester MN USA 55905 er, MN55905 USA
Citazione:
D.D. Billadeau et al., "Specific subdomains of Vav differentially affect T cell and NK cell activation", J IMMUNOL, 164(8), 2000, pp. 3971-3981

Abstract

The Vav protooncogene is a multidomain protein involved in the regulation of IL-2 gene transcription in T cells and the development of cell-mediated killing by cytotoxic lymphocytes. We have investigated the differential roles that specific protein subdomains within the Vav protooncogene have in the development of these two distinct cellular processes. Interestingly,a calponin homology (CH) domain mutant of Vav (CH-) fails to enhance NF-AT/AP-1-mediated gene transcription but is still able to regulate the development of cell-mediated killing. The inability of the CH- mutant to enhance NF-AT/AP-1-mediated transcription appears to be secondary to defective intracellular calcium, because 1) the CH- mutant has significantly reduced TCR-initiated calcium signaling, and 2) treatment with the calcium ionophore ionomycinor cotransfection with activated calcineurin restores NF-AT/AP-1-mediated gene transcription. The pleckstrin homology (PH) domain of Vav has also been implicated in regulating Vav activation. We found that deletion of the PHdomain of Vav yields a protein that can neither enhance gene transcriptionfrom the NF-AT/AP-1 reporter nor enhance TCR- or FcR-mediated killing. In contrast, the PH deletion mutant of Vav is able to regulate the developmentof natural cytotoxicity, indicating a functional dichotomy for the PH domain in the regulation of these two distinct forms of killing, Lastly, mutation of three tyrosines (Y142, Y160, and Y174) within the acidic domain of Vav has revealed a potential negative regulatory site. Replacement of all three tyrosines,vith phenylalanine results in a hyperactive protein that increases NF-AT/AP-1-mediated gene transcription and enhances cell-mediated cytotoxicity, Taken together, these data highlight the differential roles that specific subdomains of Vav have in controlling distinct cellular functions. More broadly, the data suggest that separate lymphocyte functions can potentially be modulated by domain-specific targeting of Vav and other criticalintracellular signaling molecules.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/11/20 alle ore 10:37:30