Differential activation of acute phase response factor/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130 .2. Src homology SH2 domains define the specificity of STAT factor activation
Differential activation of acute phase response factor/Stat3 and Stat1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130 .2. Src homology SH2 domains define the specificity of STAT factor activation
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DOI：
10.1074/jbc.271.22.12999
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发表时间：
1996-05-31
影响因子：
4.8
通讯作者：
Horn, F
中科院分区：
文献类型：
--
作者：
Hemmann, U;Gerhartz, C;Horn, F
STAT转录因子的不同但重叠的集合被不同的细胞因子激活。一个例子是急性期反应因子（APRF，也称为Stat 3）和Stat 1通过白细胞介素6和干扰素-γ的差异活化。白细胞介素6激活这两种因子，而至少在人类细胞中，干扰素-γ只招募Stat 1。干扰素γ激活Stat 1是通过干扰素γ受体的胞质酪氨酸基序Y 440介导的。在随附的论文（Gerhartz，C.，Hegel，B.，Sasse，J.，赫曼，美国，兰德斯角，Schneider-Mergener，J.，Horn，F.，海因里希，P. C.，和格雷夫，L.（1996）J.Biol.Chem.271，12991-12998），我们证明了白细胞介素6信号转导物gp 130的细胞质部分内的两个酪氨酸基序特异性介导APRF活化，而另外两个可以募集APRF和Stat 1。通过在COS-7细胞中表达一系列Stat 1/APRF结构域交换突变体，我们现在确定哪些Stat 1和APRF结构域参与磷酸酪氨酸基序的特异性识别。我们的数据表明，SH 2结构域是特异性STAT因子募集的唯一决定因素。此外，Stat 1的SH 2结构域能够识别两种不相关类型的磷酸酪氨酸基序，一种由干扰素-γ受体Y 440 DKPH肽表示，另一种由两个gp 130 YXPQ基序表示。通过分子模拟，我们提出了Stat 1和APRF SH 2结构域的三维模型结构，这使我们能够解释这些因子的不同结合偏好，并预测对特定肽识别至关重要的氨基酸。
Distinct yet overlapping sets of STAT transcription factors are activated by different cytokines. One example is the differential activation of acute phase response factor (APRF, also called Stat3) and Stat1 by interleukin 6 and interferon-gamma. Interleukin 6 activates both factors while, at least in human cells, interferon-gamma recruits only Stat1. Stat1 activation by interferon-gamma is mediated through a cytosolic tyrosine motif, Y440, of the interferon-gamma receptor. In an accompanying paper (Gerhartz, C., Heesel, B., Sasse, J., Hemmann, U., Landgraf, C., Schneider-Mergener, J., Horn, F., Heinrich, P. C., and Graeve, L. (1996) J. Biol. Chem. 271, 12991-12998), we demonstrated that two tyrosine motifs within the cytoplasmic part of the interleukin 6 signal transducer gp130 specifically mediate APRF activation while two others can recruit both APRF and Stat1. By expressing a series of Stat1/APRF domain swap mutants in COS-7 cells, we now determined which domains of Stat1 and APRF are involved in the specific recognition of phosphotyrosine motifs. Our data demonstrate that the SH2 domain is the sole determinant of specific STAT factor recruitment. Furthermore, the SH2 domain of Stat1 is able to recognize two unrelated types of phosphotyrosine motifs, one represented by the interferon-gamma receptor Y440DKPH peptide, and the other by two gp130 YXPQ motifs. By molecular modeling, we propose three dimensional model structures of the Stat1 and APRF SH2 domains which allow us to explain the different binding preferences of these factors and to predict amino acids crucial for specific peptide recognition.