Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation

T. L. Murphy, E. D. Geissal, J. D. Farrar, K. M. Murphy

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Stat4 is activated by the cytokines interleukin 12 and alpha interferon (IFN-α) and plays a significant role in directing development of naive CD4+ T cells to the Th1 phenotype. Signal transducers and activators of transcription (STAT) proteins undergo phosphorylation on a conserved tyrosine residue, resulting in homo-and heterodimerization, nuclear translocation, and DNA binding. Stat4 can bind to single IFN-γ-activated sites (GASs) as a dimer or bind two tandem GASs as a pair of STAT dimers, or tetramer, stabilized through N-terminal domain (N domain) interactions between dimers. We uncovered an unexpected effect of the Stat4 N domain in controlling the proximal activation of Stat4 by tyrosine phosphorylation at activated receptor complexes. Mutation of the N domain at tryptophan residue W37, predicted to interrupt N domain dimer formation, unexpectedly prevented IFN-α-induced tyrosine phosphorylation of the Stat4 monomer, blocking dimer formation and nuclear translocation. Furthermore, N domains appear to exert private STAT functions, since interchanging the N domains between Stat1 and Stat4 prevented receptor-mediated tyrosine phosphorylation in one case and interrupted STAT-specific gene activation in another. Finally, replacement of the N domain of Stat1 with that of Stat4 abrogated the normal Stat2 dependence of Stat1 phosphorylation, again suggesting the domains are not equivalent. Thus, in addition to its role in STAT tetramerization, the conserved STAT N domain appears to participate in very proximal steps of receptor-mediated ligand-induced tyrosine phosphorylation.

Original languageEnglish (US)
Pages (from-to)7121-7131
Number of pages11
JournalMolecular and Cellular Biology
Volume20
Issue number19
DOIs
StatePublished - 2000

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Transducers
Phosphorylation
Tyrosine
Interferons
STAT Transcription Factors
Activator Appliances
Interleukin-12
Interferon-alpha
Tryptophan
Transcriptional Activation
tyrosine receptor
Cytokines
Ligands
T-Lymphocytes
Phenotype
Mutation
DNA

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation. / Murphy, T. L.; Geissal, E. D.; Farrar, J. D.; Murphy, K. M.

In: Molecular and Cellular Biology, Vol. 20, No. 19, 2000, p. 7121-7131.

Research output: Contribution to journalArticle

Murphy, T. L. ; Geissal, E. D. ; Farrar, J. D. ; Murphy, K. M. / Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation. In: Molecular and Cellular Biology. 2000 ; Vol. 20, No. 19. pp. 7121-7131.
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