Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction
Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction
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DOI：
10.4049/jimmunol.169.3.1219
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Haan, S
中科院分区：
文献类型：
--
作者：
Hörtner, M;Nielsch, U;Haan, S
G-CSF是一种多肽生长因子，用于化疗后的治疗。G-CSF调节粒细胞生成并通过诱导G-CSFR的同源二聚化作用于其靶细胞，从而激活细胞内信号级联。G-CSFR在其细胞质尾区包含四个酪氨酸基序，已显示其募集许多调节蛋白。细胞因子信号转导抑制因子3（SOCS-3），也称为含丝氨酸诱导的Src同源2蛋白3，是最近发现的反馈抑制剂家族的成员，其已显示出抑制Janus激酶/STAT途径。在这项研究中，我们证明，人SOCS-3是快速诱导的G-CSF在多形核白细胞以及髓样前体细胞系U937和SOCS-3负调控G-CSFR介导的STAT激活。最重要的是，我们表明，SOCS-3招募的G-CSFR在磷酸化依赖的方式，我们确定磷酸酪氨酸（pY）729作为主要的招聘网站SOCS-3。此外，我们证明，SOCS-3直接结合到这个pY基序。表面等离子体共振分析揭示了这种相互作用的解离常数（K-D）约为2.8 μ M。这些发现有力地表明，SOCS-3向pY 729的募集对于SOCS-3调节G-CSFR介导的信号转导是重要的。
G-CSF is a polypeptide growth factor used in treatment following chemotherapy. G-CSF regulates granulopoiesis and acts on its target cells by inducing homodimerization of the G-CSFR, thereby activating intracellular signaling cascades. The G-CSFR encompasses four tyrosine motifs on its cytoplasmic tail that have been shown to recruit a number of regulatory proteins. Suppressor of cytokine signaling 3 (SOCS-3), also referred to as cytokine-inducible Src homolgy 2-containing protein 3, is a member of a recently discovered family of feedback inhibitors that have been shown to inhibit the Janus kinase/STAT pathway. In this study, we demonstrate that human SOCS-3 is rapidly induced by G-CSF in polymorphonuclear neutrophils as well as in the myeloid precursor cell line U937 and that SOCS-3 negatively regulates G-CSFR-mediated STAT activation. Most importantly, we show that SOCS-3 is recruited to the G-CSFR in a phosphorylation-dependent manner and we identify phosphotyrosine (pY)729 as the major recruitment site for SOCS-3. Furthermore, we demonstrate that SOCS-3 directly binds to this pY motif. Surface plasmon resonance analysis reveals a dissociation constant (K-D) for this interaction of around 2.8 muM. These findings strongly suggest that the recruitment of SOCS-3 to pY729 is important for the modulation of G-CSFR-mediated signal transduction by SOCS-3.