Receptor specific downregulation of cytokine signaling by autophosphorylation in the FERM domain of Jak2.
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.
Funakoshi-Tago
Megumi
M
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 3810, USA.
Pelletier
Stephane
S
Matsuda
Tadashi
T
Parganas
Evan
E
Ihle
James N
JN
D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D018121:Receptors, Cytokine / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D016207:Cytokines; D008024:Ligands; D018121:Receptors, Cytokine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2