Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.
Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.
复制标题
DOI：
10.1016/j.cell.2017.02.026
复制
发表时间：
2017-03-09
期刊：
影响因子：
64.5
通讯作者：
Sankaran VG
中科院分区：
文献类型：
--
作者：
Kim AR;Ulirsch JC;Wilmes S;Unal E;Moraga I;Karakukcu M;Yuan D;Kazerounian S;Abdulhay NJ;King DS;Gupta N;Gabriel SB;Lander ES;Patiroglu T;Ozcan A;Ozdemir MA;Garcia KC;Piehler J;Gazda HT;Klein DE;Sankaran VG
细胞因子被经典地认为是通过单调激活受体来刺激下游信号通路。我们描述了一例由细胞因子促红细胞生成素(EPO，R150Q)纯合子突变引起的严重贫血。令人惊讶的是，EPO R150Q突变体对其受体的亲和力仅略有降低，但改变了结合动力学。EPO突变体在刺激红系细胞增殖和分化方面效果较差，即使在最大有效浓度下也是如此。虽然EPO突变体可以刺激STAT5等效应器，其程度与野生型配体相似，但JAK2介导的选定下游靶标的磷酸化程度有所降低。这种下游信号的损伤机制是由于细胞外结合变化引起的受体二聚化动力学的改变。这些结果表明，单一细胞因子的变异可以导致下游信号的偏向，从而导致人类疾病。此外，我们通过突变鉴定和功能研究定义了一种独特的可治疗形式的贫血。
Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation in the cytokine erythropoietin (EPO, R150Q). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor, but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.