Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways
Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways
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DOI：
10.1182/blood-2004-10-4093
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发表时间：
2005-06-15
期刊：
影响因子：
20.3
通讯作者：
Lodish, HF
中科院分区：
文献类型：
--
作者：
Tong, W;Zhang, J;Lodish, HF
促红细胞生成素 (Epo) 及其受体 EpoR 是红细胞发育的主要调节因子。添加 Epo 后，EpoR 信号通过 Janus 激酶 2 (JAK2) 激活多种途径，包括 Stat5、磷酸肌醇 3 激酶 (PI-3K)/Akt 和 p42/44 丝裂原激活蛋白激酶 (MAPK)。接头蛋白 Lnk 参与细胞因子受体信号传导。在这里，我们发现 Link 缺陷小鼠的红系祖细胞数量增加，并且脾脏红系集落形成单位 (CFU-e) 祖细胞对 Epo 高度敏感。 Lnk(-/-) 小鼠在红细胞生成应激后也表现出优异的恢复能力。此外，Link 缺陷导致脾红细胞祖细胞中 Epo 诱导的信号通路增强。相反，Lnk 过表达会抑制 32D/EpoR 细胞中 Epo 诱导的细胞生长。在胎儿肝细胞的原代培养物中，Link 过度表达会抑制 Epo 依赖性红细胞分化并诱导细胞凋亡。 Link 阻断原代成红细胞中由 Epo 诱导的 3 条主要信号传导途径：Stat5、Akt 和 MAPK。此外，Link Src 同源 2 (SH2) 结构域对其抑制功能至关重要，而 Link 的 C 末端附近的保守酪氨酸和 pleckstrin 同源 (PH) 结构域并不重要。此外，野生型 Lnk（而非 Link SH2 突变体）在 Epo 给药后变得酪氨酸磷酸化，并抑制 EpoR 磷酸化和 JAK2 激活。因此，Link 通过其 SH2 结构域，通过减弱 JAK2 激活来负调节 EpoR 信号传导，并调节 Epo 介导的红细胞生成。 (c) 2005 年，美国血液学会。
Erythropoietin (Epo), along with its receptor EpoR, is the principal regulator of red cell development. Upon Epo addition, the EpoR signaling through the Janus kinase 2 (JAK2) activates multiple pathways including Stat5, phosphoinositide-3 kinase (PI-3K)/Akt, and p42/44 mitogen-activated protein kinase (MAPK). The adaptor protein Lnk is implicated in cytokine receptor signaling. Here, we showed that Link-deficient mice have elevated numbers of erythroid progenitors, and that splenic erythroid colony-forming unit (CFU-e) progenitors are hypersensitive to Epo. Lnk(-/-) mice also exhibit superior recovery after erythropoietic stress. In addition, Link deficiency resulted in enhanced Epo-induced signaling pathways in splenic erythroid progenitors. Conversely, Lnk overexpression inhibits Epo-induced cell growth in 32D/EpoR cells. In primary culture of fetal liver cells, Link overexpression inhibits Epo-dependent erythroblast differentiation and induces apoptosis. Link blocks 3 major signaling pathways, Stat5, Akt, and MAPK, induced by Epo in primary erythroblasts. In addition, the Link Src homology 2 (SH2) domain is essential for its inhibitory function, whereas the conserved tyrosine near the C-terminus and the pleckstrin homology (PH) domain of Link are not critical. Furthermore, wild-type Lnk, but not the Link SH2 mutant, becomes tyrosine-phosphorylated following Epo administration and inhibits EpoR phosphorylation and JAK2 activation. Hence, Link, through its SH2 domain, negatively modulates EpoR signaling by attenuating JAK2 activation, and regulates Epo-mediated erythropoiesis. (c) 2005 by The American Society of Hematology.