Core erythropoietin receptor signals for late erythroblast development
Core erythropoietin receptor signals for late erythroblast development
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DOI：
10.1182/blood-2005-02-0684
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发表时间：
2006-04-01
期刊：
影响因子：
20.3
通讯作者：
Wojchowski, DM
中科院分区：
文献类型：
--
作者：
Menon, MP;Fang, J;Wojchowski, DM
红细胞形成的关键信号是由激活的酪氨酸磷酸化的促红细胞生成素受体（EpoR）复合物转导的。尽管如此，稳定的红细胞生成是由胞质磷酸酪氨酸位点缺乏的EpoR等位基因有效支持的。为了更好地定义核心EpoR作用机制，我们首次分析了骨髓源性红母细胞中最小py0 （EpoR- hm）和py343保留（EpoR- h）等位基因的信号传导能力。通过每个等位基因激活Jak2具有可比性。通过EpoR-H诱导Stat5（和几个Stat5应答基因），但不通过EpoR-HM诱导。所有EpoR形式的Stat1和Stat3激活都是正常的。对于EpoR-HM和EpoR-H， Akt和p70s6激酶活性降低了数倍，JNK活性最低。然而，ERKs仅通过EpoR-HM被过度激活。在体内，Epo- hm小鼠的Epo表达升高，而Epo诱导的网状细胞产生减少。在体外，epr - hm红母细胞成熟也被减弱（基于DNA含量、前角光散射和血红蛋白）。这些epor - hm特异性缺陷不仅在EpoR-H中PY343位点修复后得到纠正，而且在MEK1,2抑制后也得到纠正。因此，红细胞形成的核心EpoR PY位点无关信号似乎与Stat5、Stat1、Stat3、p70s6激酶和JNK无关，但依赖于ERK。然而，野生型信号能力进一步依赖于通过EpoR/ PY343/Stat5轴提供的信号。
Critical signals for erythroblast formation are transduced by activated, tyrosine-phosphorylated erythropoietin receptor (EpoR) complexes. Nonetheless, steadystate erythropoiesis is supported effectively by EpoR alleles that are deficient in cytoplasmic phosphotyrosine sites. To better define core EpoR action mechanisms, signaling capacities of minimal PY-null (EpoR-HM) and PY343-retaining (EpoR-H) alleles were analyzed for the first time in bone marrow-derived erythroblasts. Jak2 activation via each allele was comparable. Stat5 (and several Stat5- response genes) were induced via EpoR-H but not via EpoR-HM. Stat1 and Stat3 activation was nominal for all EpoR forms. For both EpoR-HM and EpoR-H, Akt and p70S6-kinase activation was decreased multifold, and JNK activation was minimal. ERKs, however, were hyperactivated uniquely via EpoR-HM. In vivo, Epo expression in EpoR-HM mice was elevated, while Epo-induced reticulocyte production was diminished. In vitro, EpoR-HM erythroblast maturation also was attenuated (based on DNA content, forward-angle light scatter, and hemoglobinization). These EpOR-HM-specific defects were corrected not only upon PY343 site restoration in EpoR-H, but also upon MEK1,2 inhibition. Core EpoR PY site-independent signals for erythroblast formation therefore appear to be Stat5, Stat1, Stat3, p70S6-kinase, and JNK independent, but ERK dependent. Wild-type signaling capacities, however, depend further upon signals provided via an EpoR/ PY343/Stat5 axis.