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Titolo:
The oncogenic 70Z Cbl mutation blocks the phosphotyrosine binding domain-dependent negative regulation of ZAP-70 by c-Cbl in Jurkat T cells
Autore:
van Leeuwen, JEM; Paik, PK; Samelson, LE;
Indirizzi:
NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA NCI Bethesda MDUSA 20892 lar & Mol Biol Lab, NIH, Bethesda, MD 20892 USA
Titolo Testata:
MOLECULAR AND CELLULAR BIOLOGY
fascicolo: 10, volume: 19, anno: 1999,
pagine: 6652 - 6664
SICI:
0270-7306(199910)19:10<6652:TO7CMB>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
GROWTH-FACTOR RECEPTOR; PROTEIN-TYROSINE KINASE; OF-FUNCTION MUTATION; ANTIGEN-RECEPTOR; SIGNAL-TRANSDUCTION; EGF RECEPTOR; PHOSPHORYLATION SITES; DISTINCT PATHWAYS; ERBB RECEPTORS; DOMINANT ROLE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
72
Recensione:
Indirizzi per estratti:
Indirizzo: van Leeuwen, JEM NCI, Cellular & Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892USA NCI 9000 Rockville Pike Bethesda MD USA 20892 MD 20892USA
Citazione:
J.E.M. van Leeuwen et al., "The oncogenic 70Z Cbl mutation blocks the phosphotyrosine binding domain-dependent negative regulation of ZAP-70 by c-Cbl in Jurkat T cells", MOL CELL B, 19(10), 1999, pp. 6652-6664

Abstract

T-cell receptor (TCR) engagement results in the activation of Src family (Lck and Fyn) and ZAP-70 protein tyrosine kinases, leading to tyrosine phosphorylation of multiple cellular substrates including the complex adapter protein c-Cbl. Moreover, Cbl is tyrosine phosphorylated upon engagement of growth factor receptors, cytokine receptors, and immunoreceptors and functions as a negative regulator of tyrosine kinase signalling pathways. Cbl associates via its phosphotyrosine binding (PTB) domain to the ZAP-70 pY292 negative regulatory phosphotyrosine. me recently demonstrated that the oncogenic Cbl mutant, 70Z Cbl, requires its PTB domain to upregulate NFAT in unstimulated Jurkat T cells, Here, we demonstrate that kinase-dead but not wild-type forms of Fyn, Lck, and ZAP-70 block 70Z Cbl-mediated NFAT activation. Moreover, 70Z Cbl does not upregulate NFAT in the ZAP-70-deficient P116 Jurkat T-cell line. The requirement for Fyn, Lck, and ZAP-70 is not due to tyrosine phosphorylation of 70Z Cbl, as mutation of all tyrosines in, or deletion of, the C-terminal region of 70Z Cbl (amino acids 655 to 906) blocks 70ZCbl tyrosine phosphorylation but enhances 70Z Cbl-mediated NFAT activation. Further, 70Z Cbl does not cooperate with ZAP-70 Y292F to upregulate NFAT,indicating that 70Z Cbl and ZAP-70 do not activate parallel signalling pathways, Finally, the upregulation of NFAT observed upon ZAP-70 overexpression is blocked by Cbl in a PTB domain-dependent manner. We conclude that oncogenic 70Z Cbl acts as a dominant negative to block the PTB domain-dependentnegative regulatory role of endogenous Cbl on ZAP-70, leading to constitutive ZAP-70 signalling and activation of transcription factors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/11/20 alle ore 21:41:35