Journal
EMBO JOURNAL
Volume 25, Issue 20, Pages 4763-4772Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601365
Keywords
autophosphorylation; cytokine receptor; FERM domain; Jak kinases; Jak2
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Funding
- NCI NIH HHS [P30 CA021765, CA21765] Funding Source: Medline
- NHLBI NIH HHS [P01 HL53749, P01 HL053749] Funding Source: Medline
- NIDDK NIH HHS [R01 DK042932, R01 DK42932] Funding Source: Medline
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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-c.
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