Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson C D, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein D M, Penninger J M
Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Nature. 2001 Jan 18;409(6818):349-54. doi: 10.1038/35053086.
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). The transmembrane PTPase CD45 is a key regulator of antigen receptor signalling in T and B cells. 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, 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.
通过抗原、生长因子和细胞因子受体对酪氨酸磷酸化及相关信号传导的调节是由蛋白酪氨酸激酶和蛋白酪氨酸磷酸酶（PTPases）的相互作用介导的。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。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在造血谱系发育的所有阶段均高表达，这表明CD45可能调节其他细胞类型，并可能作用于其他底物。在此我们表明，CD45抑制JAK（Janus激酶）激酶，并负向调节细胞因子受体信号传导。cd45基因的靶向破坏导致细胞因子和干扰素受体介导的JAKs和STAT（信号转导子和转录激活子）蛋白的激活增强。在体外，CD45直接使JAKs去磷酸化并与之结合。在功能上，CD45在体外和体内负向调节白细胞介素-3介导的细胞增殖、促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作为一种造血JAK磷酸酶的意外且新的功能，它负向调节细胞因子受体信号传导。
