Receptor specific downregulation of cytokine signaling by autophosphorylation in the FERM domain of Jak2

Megumi Funakoshi-Tago, Stephane Pelletier, Tadashi Matsuda, Evan Parganas, James N. Ihle

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

The tyrosine kinase, Janus kinase-2 (Jak2), plays a pivotal role in signal transduction through a variety of cytokine receptors, including the receptor for erythropoietin (Epo). Although the physiological relevance of Jak2 has been definitively established, less is known about its regulation. In studies assessing the roles of sites of tyrosine phosphorylation, we identified Y 119 in the FERM (band 4.1, Ezrin, radixin and moesin) domain as a phosphorylation site. In these studies, we demonstrate that the phosphorylation of Y119 in response to Epo downregulates Jak2 kinase activity. Using a phosphorylation mimic mutation (Y119E), downregulation is shown to involve dissociation of Jak2 from the receptor complex. Conversely, a Y 119F mutant is more stably associated with the receptor complex. Thus, in cytokine responses, ligand binding induces activation of receptor associated Jak2, autophosphorylation of Y119 in the FERM domain and the subsequent dissociation of the activated Jak2 from the receptor and degradation. This regulation occurs with the receptors for Epo, thrombopoietin and growth hormone but not with the receptor for interferon-γ.

Original languageEnglish
Pages (from-to)4763-4772
Number of pages10
JournalEMBO Journal
Volume25
Issue number20
DOIs
Publication statusPublished - 2006 Oct 18

Keywords

  • Autophosphorylation
  • Cytokine receptor
  • FERM domain
  • Jak kinases
  • Jak2

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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