SIGNALING THROUGH THE INTERLEUKIN-2 RECEPTOR-BETA CHAIN ACTIVATES A STAT-5-LIKE DNA-BINDING ACTIVITY
SIGNALING THROUGH THE INTERLEUKIN-2 RECEPTOR-BETA CHAIN ACTIVATES A STAT-5-LIKE DNA-BINDING ACTIVITY
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DOI：
10.1073/pnas.92.16.7192
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发表时间：
1995-08-01
影响因子：
11.1
通讯作者：
GREENE, WC
中科院分区：
文献类型：
--
作者：
GAFFEN, SL;LAI, SY;GREENE, WC
为了探索STAT因子（“信号转导和转录激活因子”）在白细胞介素2受体（IL-2R）信号级联中的可能参与，制备了表达由红细胞生成素受体胞外结构域融合到IL-2R β或- γ (c)链细胞质结构域的嵌合受体的小鼠HT-2细胞。促红细胞生成素或IL-2激活这些细胞导致dna结合活性的快速核表达，与选定的STAT反应元件反应。根据与特异性抗stat抗体的反应性，这种dna结合活性被鉴定为STAT-5的小鼠同源物。加入酪氨酸激酶抑制剂herbimycin A可以阻断这种stat -5样因子的核表达，但加入il -2诱导增殖的亲免疫蛋白结合拮抗剂rapamycin则不能。IL-2R β链似乎对il -2诱导的STAT-S激活至关重要，因为缺乏所有细胞质酪氨酸残基的突变β链无法诱导这种DNA结合。相反，缺乏所有细胞质酪氨酸残基的γ (c)突变体被证明完全能够诱导STAT-5， STAT-5与IL-2R β中功能重要的酪氨酸残基的物理结合被发现支持，与IL-2R β尾部Y392和Y510序列对应的磷酸化（而非非磷酸化）肽特异性抑制STAT-5 DNA结合。
To explore the possible involvement of STAT factors (''signal transducers and activators of transcription'') in the interleukin 2 receptor (IL-2R) signaling cascade, murine HT-2 cells expressing chimeric receptors composed of the extracellular domain of the erythropoietin receptor fused to the cytoplasmic domains of the IL-2R beta or -gamma(c) chains were prepared. Erythropoietin or IL-2 activation of these cells resulted in rapid nuclear expression of a DNA-binding activity that reacted with select STAT response elements. Based on reactivity with specific anti-STAT antibodies, this DNA-binding activity was identified as a murine homologue of STAT-5. Induction of nuclear expression of this STAT-5-like factor was blocked by the addition of herbimycin A, a tyrosine kinase inhibitor, but not by rapamycin, an immunophilin-binding antagonist of IL-2-induced proliferation. The IL-2R beta chain appeared critical for IL-2-induced activation of STAT-S, since a mutant beta chain lacking all cytoplasmic tyrosine residues was incapable of inducing this DNA binding. In contrast, a gamma(c) mutant lacking all of its cytoplasmic tyrosine residues proved fully competent for the induction of STAT-5, Physical binding of STAT-5 to functionally important tyrosine residues within IL-2R beta was supported by the finding that phosphorylated, but not nonphosphorylated, peptides corresponding to sequences spanning Y392 and Y510 of the IL-2R beta tail specifically inhibited STAT-5 DNA binding.