Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: Structural receptor requirements for signal attenuation
Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: Structural receptor requirements for signal attenuation
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DOI：
10.4049/jimmunol.165.5.2535
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发表时间：
2000-09-01
影响因子：
4.4
通讯作者：
Schaper, F
中科院分区：
文献类型：
--
作者：
Anhuf, D;Weissenbach, M;Schaper, F
IL-6 R复合物的刺激导致含有Src同源结构域的酪氨酸磷酸酶2（SHP 2）募集至受体亚基gp 130及其随后的酪氨酸磷酸化。SHP 2是一种含有两个SH 2结构域的蛋白酪氨酸磷酸酶，可被许多细胞因子和生长因子激活。SHP 2抵消STAT家族转录因子的激活和IL-6应答基因的诱导。gp 130的酪氨酸759是IL-6 R复合物的信号转导亚基，对SHP 2的磷酸化至关重要。酪氨酸759突变为苯丙氨酸导致IL-6依赖性基因的诱导增强。在这里，我们证明，没有进一步的酪氨酸在gp 130的胞质部分所需的磷酸化SHP 2。我们还测试了是否酪氨酸759基序在两个亚基的gp 130二聚体所需的SHP 2协会和酪氨酸磷酸化。有趣的是，在gp 130二聚体的单链中的一个SHP 2募集磷酸酪氨酸基序足以介导SHP 2与gp 130受体亚基的结合及其酪氨酸磷酸化，以及减弱IL-6依赖性基因诱导。此外，我们表明，通过Y 759抑制基因诱导不需要在同一受体亚基内存在SHP 2和STAT募集位点，但在同一受体复合物内。gp 130中的Y 759基序也减弱了由抑瘤素M和白血病抑制因子受体复合物介导的基因诱导，这两种复合物都含有gp 130作为共享亚基。
Stimulation of the IL-6R complex leads to Src homology domain containing tyrosine phosphatase 2 (SHP2) recruitment to the receptor subunit gp130 and its subsequent tyrosine phosphorylation. SHP2 is a two-SH2 domain-containing protein tyrosine phosphatase that is activated by many cytokines and growth factors. SHP2 counteracts the activation of transcription factors of the STAT family and the induction of IL-6-responsive genes. Tyrosine 759 of gp130, the signal transducing subunit of the IL-6R complex, is essential for the phosphorylation of SHP2. Mutation of tyrosine 759 to phenylalanine leads to an enhanced inducibility of IL-6-dependent genes. Here we demonstrate that no further tyrosines in the cytoplasmic part of gp130 are required for the phosphorylation of SHP2. We also tested whether the tyrosine 759 motifs in both subunits of the gp130 dimer are required for SHP2 association and tyrosine phosphorylation. Interestingly, one SHP2-recruiting phosphotyrosine motif in a single chain of the gp130 dimer is sufficient to mediate SHP2 association to the gp130 receptor subunit and its tyrosine phosphorylation as well as to attenuate IL-6-dependent gene induction. Furthermore, we show that repression of gene induction via Y759 does not require the presence of the SHP2 and STAT recruitment sites within the same receptor subunit, but within the same receptor complex. The Y759 motif in gp130 also attenuates gene induction mediated by the oncostatin M and leukemia inhibitory factor receptor complexes, which both contain gp130 as the shared subunit.