ZAP-70 tyrosines 315 and 492 transmit non-genomic glucocorticoid (GC) effects in T cells

F. Boldizsár, M. Szabo, K. Kvell, T. Czömpöly, G. Talaber, J. Bjorkan, D. Bartis, P. Németh, T. Berki

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

ZAP-70 kinase is a key regulator of early T-cell signaling; moreover, it also participates in non-genomic glucocorticoid (GC) signaling. Short-term high-dose GC-analogue treatment induces the phosphorylation of the kinase, and its association with the GC receptor (GR).In the present work, first, we identified those tyrosine (Y) residues of the ZAP-70 kinase which were involved in non-genomic GC signaling using an array of P116 cells (ZAP-70-deficient Jurkat subclone) lentivirally-transfected with wild type or point-mutated ZAP-70 constructs where Y-residues were replaced with phenylalanine (F) at positions 069, 126, 178, 238, 292, 315, 492 or 493. Then, we characterized the GC-analogue-induced Y-phosphorylation of 3 key substrates of the ZAP-70 kinase: SLP-76, LAT and Cbl. Finally, we studied the cross talk between the non-genomic GC- and TcR/CD3 signaling pathways.Y-F mutations at positions 315 or 492 abolished the short high-dose Dexamethasone (DX) treatment-induced ZAP-70 phosphorylation suggesting that these Y-residues were involved in ZAP-70-mediated non-genomic GC actions. DX treatment alone induced Y-phosphorylation of LAT, SLP-76 and Cbl; moreover, in F315- and F492-ZAP-70 mutated cells decreased DX-induced Y-phosphorylation of SLP-76 and Cbl was observed indicating that these molecules might transmit downstream non-genomic GC signals in a ZAP-70 dependent manner. Short, high dose DX treatment influenced significantly the anti-CD3-induced signaling events: we observed alterations in LAT, SLP-76 and Cbl Y-phosphorylation and a decreased Ca2+-signal.These results confirm that ZAP-70 represents an important link between the non-genomic GC and TcR/CD3 signaling pathways. Importantly, the DX-induced effects on resting and activated T-cells are differentially mediated. These fine molecular details help to better understand the complex mechanism of non-genomic GC effects in T-cells.

Original languageEnglish
Pages (from-to)111-117
Number of pages7
JournalMolecular Immunology
Volume53
Issue number1-2
DOIs
Publication statusPublished - Jan 2013

Fingerprint

Glucocorticoids
Tyrosine
T-Lymphocytes
ZAP-70 Protein-Tyrosine Kinase
Dexamethasone
Phosphorylation
Glucocorticoid Receptors
Phenylalanine
Phosphotransferases
Mutation

Keywords

  • Cbl
  • Non-genomic GC action
  • SLP-76
  • TcR signaling
  • ZAP-70

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

ZAP-70 tyrosines 315 and 492 transmit non-genomic glucocorticoid (GC) effects in T cells. / Boldizsár, F.; Szabo, M.; Kvell, K.; Czömpöly, T.; Talaber, G.; Bjorkan, J.; Bartis, D.; Németh, P.; Berki, T.

In: Molecular Immunology, Vol. 53, No. 1-2, 01.2013, p. 111-117.

Research output: Contribution to journalArticle

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AU - Talaber, G.

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AU - Németh, P.

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