Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands.
Tuning cytokine receptor signaling by re-orienting dimer geometry with surrogate ligands.
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DOI：
10.1016/j.cell.2015.02.011
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发表时间：
2015-03-12
期刊：
影响因子：
64.5
通讯作者：
Garcia KC
中科院分区：
文献类型：
--
作者：
Moraga I;Wernig G;Wilmes S;Gryshkova V;Richter CP;Hong WJ;Sinha R;Guo F;Fabionar H;Wehrman TS;Krutzik P;Demharter S;Plo I;Weissman IL;Minary P;Majeti R;Constantinescu SN;Piehler J;Garcia KC
细胞因子和生长因子的大多数细胞表面受体以二聚体形式发出信号，但目前尚不清楚重塑受体二聚体拓扑结构是否是“调节”信号输出的可行策略。我们利用双抗体（DA）作为原型二聚体受体-配体系统（细胞因子促红细胞生成素及其受体（EpoR））中的替代配体，以使非天然结构中的EpoR胞外域二聚化。Diabody诱导的信号幅度从完全到最小激动变化，并且DA/EpoR复合物的结构在EpoR二聚体取向和接近度上不同。与EPO相比，双抗体还引起信号传导途径和基因表达谱的偏倚或差异活化。非信号传导双抗体抑制来自骨髓增生性肿瘤患者的红系前体细胞增殖，这是由于组成型活性JAK 2 V617 F突变。因此，引起配体非依赖性受体激活的细胞内致癌突变可以被细胞外配体抵消，细胞外配体将受体重新定向为无活性的二聚体拓扑结构。这种方法对于调节许多二聚体受体系统的信号输出具有广泛的应用。称为双抗体的合成配体可以改变信号激活的幅度和性质，或通过重新定向受体二聚化的几何结构来抵消致癌配体非依赖性细胞内信号传导。
Most cell surface receptors for cytokines and growth factors signal as dimers, but it is unclear if remodeling receptor dimer topology is a viable strategy to ‘tune’ signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitude varied from full to minimal agonism, and structures of the DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased, or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems. Synthetic ligands called diabodies can change the amplitude and nature of signal activation, or counteract oncogenic ligand-independent intracellular signaling, by reorienting the geometry of receptor dimerization.