Induction of Jak/STAT signaling by activation of the type 1 TNF receptor.
Induction of Jak/STAT signaling by activation of the type 1 TNF receptor.
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DOI：
10.4049/jimmunol.160.6.2742
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发表时间：
1998-03
影响因子：
4.4
通讯作者：
D. Guo;J. Dunbar;Chuanhe Yang;L. Pfeffer;D. Donner
中科院分区：
文献类型：
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作者：
D. Guo;J. Dunbar;Chuanhe Yang;L. Pfeffer;D. Donner
细胞对肿瘤坏死因子的反应是由两种细胞表面受体之一启动的，即1型肿瘤坏死因子受体(TNFR1)和2型肿瘤坏死因子受体(TNFR2)。尽管这两种受体都不包含固有的蛋白酪氨酸激酶，但这种活性与肿瘤坏死因子的作用有关。在这项研究中，我们证明了小鼠肿瘤坏死因子诱导3T3-L1脂肪细胞内Janus酪氨酸激酶JAK1、JAK2和TYK2的酪氨酸磷酸化和激活。在3T3-L1脂肪细胞中，肿瘤坏死因子激活Jak激酶与STAT1、STAT3、STAT5和STAT6的酪氨酸磷酸化有关，而与STAT2或STAT4无关，这表明肿瘤坏死因子作用于这些潜在的细胞质转录因子的特定亚群。TNFR1激动剂抗血清可诱导Jak蛋白和STAT蛋白的磷酸化。人肿瘤坏死因子可选择性地与小鼠细胞上的肿瘤坏死因子受体1结合，从而诱导Jak蛋白的磷酸化。含肿瘤坏死因子受体1胞浆结构域的谷胱甘肽S转移酶融合蛋白从无细胞体系和3T3-L1脂肪细胞裂解产物中沉淀35S标记的JAK蛋白。这些结果表明，TNFR1的胞质结构域可以直接与JAK激酶相互作用并与其形成信号复合体。用抗TNFR1的抗血清将JAK2从HeLa细胞中沉淀出来，直接证明了它们在体内的相互作用。因此，肿瘤坏死因子通过TNFR1激活JAK/STAT信号转导通路。
Cellular responses to TNF are initiated by either of two cell surface receptors, the type 1 TNF receptor (TNFR1) and the type 2 TNF receptor (TNFR2). Although neither receptor contains an intrinsic protein tyrosine kinase, such activity has been implicated in TNF action. In this study, we show that murine TNF induces the tyrosine phosphorylation and activation of the intracellular Janus tyrosine kinases Jak1, Jak2, and Tyk2 in murine 3T3-L1 adipocytes. Activation of Jak kinases by TNF was associated with tyrosine phosphorylation of STAT1, STAT3, STAT5, and STAT6, but not STAT2 or STAT4, showing that TNF acts on a specific subset of these latent cytoplasmic transcription factors in 3T3-L1 adipocytes. Agonist antiserum to TNFR1 induced Jak kinase and STAT protein phosphorylation. Phosphorylation of Jak proteins was also induced by human TNF, which selectively binds to TNFR1 on murine cells. 35S-labeled Jak kinases were precipitated from a cell-free system and from lysates of 3T3-L1 adipocytes by a glutathione S-transferase fusion protein containing the cytoplasmic domain of TNFR1. These results suggest that the cytoplasmic domain of TNFR1 can directly interact with and form signaling complexes with Jak kinases. Jak2 was precipitated from HeLa cells by antiserum to TNFR1, directly demonstrating their association in vivo. Thus, TNF activates a Jak/STAT signal-transduction cascade by acting through TNFR1.