TYK2 and JAR2 are substrates of protein-tyrosine phosphatase 1B.
TYK2 and JAR2 are substrates of protein-tyrosine phosphatase 1B.
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DOI：
10.1074/jbc.c100583200
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发表时间：
2001-12-21
影响因子：
4.8
通讯作者：
Tonks, NK
中科院分区：
文献类型：
--
作者：
Myers, MP;Andersen, JN;Tonks, NK
蛋白质的可逆酪氨酸磷酸化由蛋白质酪氨酸激酶和蛋白质酪氨酸磷酸酶（PTPs）的协调作用调节，调节细胞对多种刺激的反应。已经确定蛋白激酶具有离散的底物组，并且底物识别通常由共有磷酸化位点的存在决定。在这里，我们已经将这一概念扩展到PTPs，并证明（E/D）-pY-pY-（R/K）是PTP 1B的共有底物识别基序。我们已经证明JAK 2和TYK 2是PTP 1B的底物，并且这些激酶内的底物识别位点与先前在胰岛素受体内鉴定的去磷酸化位点相似。PTP 1B的底物捕获突变体在干扰素刺激下与JAK 2和TYK 2形成稳定的相互作用。野生型或底物捕获突变体PTP 1B的表达抑制干扰素依赖性转录激活。最后，PTP 1B缺陷的小鼠胚胎成纤维细胞显示酪氨酸磷酸化的细微变化，包括JAK 2的过度磷酸化。密切相关的JAK家族成员JAK 1与共有去磷酸化位点不匹配，因此未被识别为底物。这些数据表明，PTP 1B可能是一个重要的细胞因子信号转导的生理调节，它可能是可能的，以获得共识底物识别基序的其他成员的PTP家族，然后可用于预测新的生理基板。
The reversible tyrosine phosphorylation of proteins, modulated by the coordinated actions of protein-tyrosine kinases and protein-tyrosine phosphatases (PTPs), regulates the cellular response to a wide variety of stimuli. It is established that protein kinases possess discrete sets of substrates and that substrate recognition is often dictated by the presence of consensus phosphorylation sites. Here, we have extended this concept to the PTPs and demonstrated that (E/D)-pY-pY-(R/K) is a consensus substrate recognition motif for PTP1B. We have shown that JAK2 and TYK2 are substrates of PTP1B and that the substrate recognition site within theses kinases is similar to the site of dephosphorylation previously identified within the insulin receptor. A substrate-trapping mutant of PTP1B formed a stable interaction with JAK2 and TYK2 in response to interferon stimulation. Expression of wild type or substrate-trapping mutant PTP1B inhibited interferon-dependent transcriptional activation. Finally, mouse embryo fibroblasts deficient in PTP1B displayed subtle changes in tyrosine phosphorylation, including hyperphosphorylation of JAK2. The closely related JAK family member, JAK1, which does not match the consensus dephosphorylation site, was not recognized as a substrate. These data illustrate that PTP1B may be an important physiological regulator of cytokine signaling and that it may be possible to derive consensus substrate recognition motifs for other members of the PTP family, which may then be used to predict novel physiological substrates.