CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling
CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling
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DOI：
10.1038/35053086
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发表时间：
2001-01-18
期刊：
影响因子：
64.8
通讯作者：
Penninger, JM
中科院分区：
文献类型：
--
作者：
Irie-Sasaki, J;Sasaki, T;Penninger, JM
蛋白酪氨酸激酶和蛋白酪氨酸磷酸酶（PTPases）的相互作用介导了抗原、生长因子和细胞因子受体对酪氨酸磷酸化和相关信号传导的调节(1)。跨膜PTPase CD45是T细胞和B细胞中抗原受体信号传导的关键调节因子（2,3）。src家族激酶已被确定为CD45的主要分子靶点（参考文献4）。然而，CD45在所有造血谱系的所有发育阶段都是高表达的(5)，这表明CD45可以调节其他细胞类型，并可能作用于其他底物。在这里，我们发现CD45抑制JAK （Janus激酶）激酶并负性调节细胞因子受体信号传导。靶向破坏cd45基因可增强细胞因子和干扰素受体介导的JAKs和STAT（信号传导和转录激活因子）蛋白的激活。在体外，CD45直接去磷酸化并与jak结合。在功能上，CD45在体外和体内负调控白介素-3介导的细胞增殖、红细胞生成素依赖性造血和抗病毒反应。我们的数据确定了CD45作为一种负调节细胞因子受体信号的造血JAK磷酸酶的意想不到的新功能。
The regulation of tyrosine phosphorylation and associated signalling through antigen, growth-factor and cytokine receptors is mediated by the reciprocal activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPases)(1). The transmembrane PTPase CD45 is a key regulator of antigen receptor signalling in T and B cells(2,3). Src-family kinases have been identified as primary molecular targets for CD45 (ref. 4). However, CD45 is highly expressed in all haematopoietic lineages at all stages of development(5), indicating that CD45 could regulate other cell types and might act on additional substrates. Here we show that CD45 suppresses JAK (Janus kinase) kinases and negatively regulates cytokine receptor signalling. Targeted disruption of the cd45 gene leads to enhanced cytokine and interferon-receptor-mediated activation of JAKs and STAT (signal transducer and activators of transcription) proteins. In vitro, CD45 directly dephosphorylates and binds to JAKs. Functionally, CD45 negatively regulates interleukin-3-mediated cellular proliferation, erythropoietin-dependent haematopoieisis and antiviral responses in vitro and in vivo. Our data identify an unexpected and novel function for CD45 as a haematopoietic JAK phosphatase that negatively regulates cytokine receptor signalling.