Receptor specific downregulation of cytokine signaling by autophosphorylation in the FERM domain of Jak2
Receptor specific downregulation of cytokine signaling by autophosphorylation in the FERM domain of Jak2
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DOI：
10.1038/sj.emboj.7601365
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发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Ihle, James N.
中科院分区：
文献类型：
--
作者：
Funakoshi-Tago, Megumi;Pelletier, Stephane;Ihle, James N.
酪氨酸激酶JAK2通过包括促红细胞生成素受体(EPO)在内的多种细胞因子受体在信号转导中发挥关键作用。虽然JAK2的生理相关性已经确定，但对它的调控知之甚少。在评估酪氨酸磷酸化位点的作用的研究中，我们确定FERM(带4.1，Ezrin，Radix和Moesin)结构域的Y-119是一个磷酸化位点。在这些研究中，我们证明了EPO对Y-119的磷酸化反应下调了JAK2激酶的活性。使用磷酸化模拟突变(Y-119E)，下调涉及JAK2从受体复合体中解离。相反，Y-119F突变体与受体复合体的联系更稳定。因此，在细胞因子反应中，配体结合诱导受体相关JAK2的激活，FERM结构域中Y-119的自动磷酸化，以及随后激活的JAK2与受体的解离和降解。这种调节发生在EPO、血小板生成素和生长激素的受体上，而不是干扰素-c的受体上。
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.