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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >CSF-1 receptor structure/function in MacCsf1r-/- macrophages: regulation of proliferation, differentiation, and morphology.
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CSF-1 receptor structure/function in MacCsf1r-/- macrophages: regulation of proliferation, differentiation, and morphology.

机译：MacCsf1r-/-巨噬细胞中的CSF-1受体结构/功能：调节增殖，分化和形态。

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摘要

CSF-1 is the major regulator of tissue macrophage development and function. A GM-CSF-dependent, CSF-1 receptor (CSF-1R)-deficient F4/80(hi)Mac-1(+)Gr1(-)CD11c(+) bone marrow macrophage (BMM) line (MacCsf1r-/-) was developed to study the roles of the eight intracellular CSF-1R tyrosines phosphorylated upon receptor activation. Retroviral expression of the wild-type CSF-1R rescued the CSF-1-induced survival, proliferation, differentiation, and morphological characteristics of primary BMM. Mutation of all eight tyrosines failed to rescue, whereas the individual Y --> F mutants (544, 559, 697, 706, 721, 807, 921, 974) rescued these CSF-1-inducible phenotypes to varying degrees. The juxtamembrane domain Y559F and activation loop Y807F mutations severely compromised proliferation and differentiation, whereas Y706, Y721F, and Y974F mutations altered morphological responses, and Y706F increased differentiation. Despite their retention of significant in vitro tyrosine kinase activity, Y559F and Y807F mutants exhibited severely impaired in vivo receptor tyrosine phosphorylation, consistent with the existence of cellular mechanisms inhibiting CSF-1R tyrosine phosphorylation that are relieved by phosphorylation of these two sites. The MacCsf1r-/- macrophage line will facilitate genetic and proteomic approaches to CSF-1R structure/function studies in the major disease-related CSF-1R-expressing cell type.
机译：CSF-1是组织巨噬细胞发育和功能的主要调节剂。依赖GM-CSF的CSF-1受体（CSF-1R）缺失的F4 / 80（hi）Mac-1（+）Gr1（-）CD11c（+）骨髓巨噬细胞（BMM）系（MacCsf1r-/- ）被开发来研究八种细胞内CSF-1R酪氨酸在受体激活后被磷酸化的作用。野生型CSF-1R的逆转录病毒表达挽救了CSF-1诱导的原发性BMM的存活，增殖，分化和形态特征。所有八个酪氨酸的突变均无法挽救，而单个Y-> F突变体（544、559、697、706、721、807、921、974）在不同程度上挽救了这些CSF-1诱导型。近膜域Y559F和激活环Y807F突变严重损害了增殖和分化，而Y706，Y721F和Y974F突变改变了形态学反应，而Y706F增加了分化。尽管它们保留了显着的体外酪氨酸激酶活性，Y559F和Y807F突变体仍表现出严重的体内受体酪氨酸磷酸化受损，这与抑制CSF-1R酪氨酸磷酸化的细胞机制的存在相一致，而这两个位点的磷酸化可以缓解这种机制。 MacCsf1r-/-巨噬细胞系将促进在与疾病相关的主要表达CSF-1R的主要细胞类型中进行CSF-1R结构/功能研究的遗传和蛋白质组学方法。

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