Jak3-independent trafficking of the common γ chain receptor subunit:: Chaperone function of Jaks revisited
Jak3-independent trafficking of the common γ chain receptor subunit:: Chaperone function of Jaks revisited
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DOI：
10.1128/mcb.24.11.5039-5049.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
O'Shea, JJ
中科院分区：
文献类型：
--
作者：
Hofmann, SR;Lam, AQ;O'Shea, JJ
Janus激酶（Jaks）在细胞因子信号传导中起重要作用，并且已报道调节其同源受体的质膜表达。在这项研究中，我们研究了Jak 3和共同的γ链（gamma（c））β是否调节其质膜表达。与白细胞介素-2R α相反，γ（c）在质膜上的定位较差，并在内体-溶酶体隔室中积累。然而，γ（c）在缺乏Jak 3的细胞表面上以相当的水平表达，并且γ（c）的质膜周转与Jak 3无关。尽管如此，Jak 3的过表达增强了γ（c）在质膜上的积累。在没有γ（c）的情况下，Jak 3定位于胞质溶胶中，而在受体存在的情况下，它与γ（c）共定位于内体和质膜中。尽管Jak FERM结构域对于受体结合是必要且足够的，但γ（c）膜运输中对全长Jak 3的要求是非常严格的;使用截短和缺失突变体，我们表明需要整个Jak 3分子，尽管激酶活性不是。因此，与其他细胞因子受体不同，γ（c）不需要Jak 3来表达受体膜。然而，全长Jak 3是正常运输细胞因子受体/Jak对所必需的，这一发现具有重要的结构和临床意义。
Janus kinases (Jaks) play an essential role in cytokine signaling and have been reported to regulate plasma membrane expression of their cognate receptors. In this study, we examined whether Jak3 and the common gamma chain (gamma(c)) reciprocally regulate their plasma membrane expression. In contrast to interleukin-2Ralpha, gamma(c) localized poorly to the plasma membrane and accumulated in endosomal-lysosomal compartments. However, gamma(c) was expressed at comparable levels on the surface of cells lacking Jak3, and plasma membrane turnover of gamma(c) was independent of Jak3. Nonetheless, overexpression of Jak3 enhanced accumulation of gamma(c) at the plasma membrane. Without gamma(c), Jak3 localized in the cytosol, whereas in the presence of the receptor, it colocalized with gamma(c) in endosomes and at the plasma membrane. Although the Jak FERM domain is necessary and sufficient for receptor binding, the requirement for full-length Jak3 in gamma(c) membrane trafficking was remarkably stringent; using truncation and deletion mutants, we showed that the entire Jak3 molecule was required, although kinase activity was not. Thus, unlike other cytokine receptors, gamma(c) does not require Jak3 for receptor membrane expression. However, full-length Jak3 is required for normal trafficking of this cytokine receptor/Jak pair, a finding that has important structural and clinical implications.