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

EMBO J. 2006 Oct 18;25(20):4763-72. doi: 10.1038/sj.emboj.7601365. Epub 2006 Oct 5.

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 Y(119) in response to Epo downregulates Jak2 kinase activity. Using a phosphorylation mimic mutation (Y(119)E), downregulation is shown to involve dissociation of Jak2 from the receptor complex. Conversely, a Y(119)F mutant is more stably associated with the receptor complex. Thus, in cytokine responses, ligand binding induces activation of receptor associated Jak2, autophosphorylation of Y(119) 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-gamma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cell Line
  • Cytokines / metabolism
  • Humans
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism*
  • Ligands
  • Mice
  • Mice, Transgenic
  • Mutation, Missense
  • Phosphorylation
  • Protein Binding / genetics
  • Protein Processing, Post-Translational* / genetics
  • Protein Structure, Tertiary / genetics
  • Receptors, Cytokine / agonists
  • Receptors, Cytokine / metabolism*
  • Signal Transduction* / genetics

Substances

  • Cytokines
  • Ligands
  • Receptors, Cytokine
  • Jak2 protein, mouse
  • Janus Kinase 2