Erythropoietin hypersensitivity in primary familial and congenital polycythemia:: Role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain
Erythropoietin hypersensitivity in primary familial and congenital polycythemia:: Role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain
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DOI：
10.1016/j.bbadis.2005.03.003
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发表时间：
2005-04-15
影响因子：
6.2
通讯作者：
Karayal, AF
中科院分区：
文献类型：
--
作者：
Arcasoy, MO;Karayal, AF
在一些原发性家族性先天性红细胞增多症 (PFCP) 患者中，促红细胞生成素受体 (EPOR) 基因突变导致 EPOR 的细胞质羧基末端区域截短，PFCP 是一种以孤立性红细胞增多症和红细胞祖细胞对 Epo 敏感性增加为特征的疾病。我们研究了 EPOR 在 PFCP 发病机制中的作用以及细胞质内酪氨酸残基 Y-285 和 Y-344 在 Epo 超敏表型产生中的需求。利用逆转录病毒介导的基因转移，对白细胞介素 3 依赖性造血细胞进行工程改造，使其表达变异的人类 EPOR。我们在 EPOR-ME 中引入酪氨酸取代苯丙氨酸，EPOR-ME 是一种天然存在的突变型人 EPOR (G5881T)，被 110 个羧基末端氨基酸截短，与常染色体显性遗传 PFCP 相关。与表达野生型EPOR的细胞相比，表达EPOR-ME的细胞表现出增加的Epo敏感性。单独的 Y-285 突变对 Epo 超敏性的影响相对较小，而 Y-344 突变则导致 Epo 敏感性丧失。酪氨酸缺失的截短 EPOR 的表达进一步降低了 Epo 介导的增殖，表明 Y-285 和 Y-344 可能有助于增殖信号。在 EPOR-ME 中，Epo 诱导的 Stat5 酪氨酸磷酸化需要 Y-344。 Y-285 或 Y-344 对细胞增殖的积极作用与 Epo 诱导的 Stat1 酪氨酸磷酸化有关。这些发现表明，EPOR-ME 细胞质结构域中的酪氨酸残基 Y-285 和 Y-344 可能有助于增加 Epo 敏感性，这是 PFCP 表型的特征。 (c) 2005 Elsevier B.V. 保留所有权利。
Erythropoietin receptor (EPOR) gene mutations leading to truncations of the cytoplasmic, carboxy-terminal region of EPOR have been described in some patients with primary familial and congenital polycythemia (PFCP), a disorder characterized by isolated erythrocytosis and increased sensitivity of erythroid progenitors to Epo. We studied the role of EPOR in the pathogenesis of PFCP and the requirement for intracytoplasmic tyrosine residues Y-285 and Y-344 in generation of Epo hypersensitivity phenotype. Interleukin-3-dependent hematopoietic cells were engineered to express variant human EPORs using retrovirus-mediated gene transfer. We introduced tyrosine to phenylalanine substitutions in EPOR-ME, a naturally occurring, mutant human EPOR (G5881T), truncated by 110 carboxy-terminal amino acids and associated with autosomal dominantly inherited PFCP. Cells expressing EPOR-ME exhibited increased Epo sensitivity compared to cells expressing wild type EPOR. Mutation of Y-285 alone had a relatively minor effect on Epo hypersensitivity whereas mutation of Y-344 resulted in loss of increased Epo sensitivity. Expression of a tyrosine-null truncated EPOR conferred further decrease of Epo-mediated proliferation suggesting that both Y-285 and Y-344 may contribute to proliferation signals. In the context of EPOR-ME, Y-344 was required for Epo-induced Stat5 tyrosine phosphorylation. The positive effect of either Y-285 or Y-344 on cellular proliferation was associated with Epo-induced tyrosine phosphorylation of Stat1. These findings suggest that both tyrosine residues Y-285 and Y-344 in the cytoplasmic domain of EPOR-ME may contribute to increased Epo sensitivity that is characteristic of PFCP phenotype. (c) 2005 Elsevier B.V. All rights reserved.