Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor gamma(c) chain for Janus kinase activation leading to T cell proliferation.
Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor gamma(c) chain for Janus kinase activation leading to T cell proliferation.
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需要来自白细胞介素 2 受体 γ(c) 链近膜区域的初始信号，激活 Janus 激酶，从而导致 T 细胞增殖。
DOI：
10.1073/pnas.94.5.1878
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发表时间：
1997
影响因子：
11.1
通讯作者：
Greenberg,PD
中科院分区：
文献类型：
--
作者：
Nelson,BH;McIntosh,BC;Rosencrans,LL;Greenberg,PD
白细胞介素2受体（IL-2 R）通过配体诱导的两条链IL-2 R β和γc的异源二聚化在T淋巴细胞中产生增殖信号，这两条链分别与酪氨酸激酶Jak 1和Jak 3相关。遗传和分子研究表明，Jak 3是γ c链的促有丝分裂信号所必需的;因为它也是已知与γc结合的唯一分子，我们推测Jak 3可能足以通过该链进行信号传导。因此，构建了融合蛋白，其中γ c的全部或部分胞质结构域被Jak 3取代。在IL-2依赖性T细胞系CTLL-2中使用嵌合IL-2 R β和γ c链评价信号传导，嵌合IL-2 R β和γ c链结合细胞因子粒细胞-巨噬细胞集落刺激因子并被其激活。在胞质结构域中仅含有Jak 3的嵌合γ c链不能介导CTLL-2细胞的增殖，但是添加与Jak 3串联的γcin的保守的近膜（PROX）结构域完全重建γ c功能。对PROX结构域的需求反映了Jak 3在体内活化中的重要作用。尽管缺乏明确的催化基序，PROX诱导早期Jak非依赖性信号，包括IL-2 R β和酪氨酸磷酸酶SHP-2的酪氨酸磷酸化。这些结果确定了γ c的最小信号成分，并提出了IL-2 R响应配体而启动信号传导的新机制。
The interleukin 2 receptor (IL-2R) generates proliferative signals in T lymphocytes by ligand-induced heterodimerization of two chains, IL-2Rβ and γc, which associate with the tyrosine kinases Jak1 and Jak3, respectively. Genetic and molecular studies have demonstrated that Jak3 is essential for mitogenic signaling by the γcchain; because it is also the only molecule known to associate with γc, we speculated that Jak3 might be sufficient for signaling by this chain. Therefore, fusion proteins were constructed in which all or part of the cytoplasmic domain of γcwas replaced by Jak3. Signaling was evaluated in the IL-2-dependent T cell line CTLL-2 using chimeric IL-2Rβ and γcchains that bind and are activated by the cytokine granulocyte–macrophage colony-stimulating factor. Chimeric γcchains containing only Jak3 in the cytoplasmic domain failed to mediate proliferation of CTLL-2 cells, but addition of a conserved membrane-proximal (PROX) domain of γcin tandem with Jak3 fully reconstituted γcfunction. The requirement for the PROX domain reflected an essential role in the activation of Jak3in vivo. Despite lacking defined catalytic motifs, PROX induced an early Jak-independent signal, including tyrosine phosphorylation of IL-2Rβ and the tyrosine phosphatase SHP-2. The results define the minimal signaling components of γcand suggest a new mechanism by which the IL-2R initiates signaling in response to ligand.