Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.
Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.
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DOI：
10.1038/nature11095
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发表时间：
2012-05-30
期刊：
影响因子：
64.8
通讯作者：
Zhang, Cheng Cheng
中科院分区：
文献类型：
--
作者：
Zheng, Junke;Umikawa, Masato;Cui, Changhao;Li, Jiyuan;Chen, Xiaoli;Zhang, Chaozheng;Hyunh, HoangDinh;Kang, Xunlei;Silvany, Robert;Wan, Xuan;Ye, Jingxiao;Canto, Alberto Puig;Chen, Shu-Hsia;Wang, Huan-You;Ward, E. Sally;Zhang, Cheng Cheng
环境因素如何通过表面受体调节成体干细胞和癌细胞的活性还知之甚少。血管生成素样蛋白（Angiopoietin-like proteins，ANGPTLs）是一个由七种分泌型糖蛋白组成的家族，在体外和体内支持造血干细胞（hematopoietic stem cells，HSC）的活性。ANGPTL在脂质代谢、血管生成和炎症中也具有重要作用，但被认为是“孤儿配体”，因为没有鉴定出受体。在这里，我们表明，免疫抑制受体人白细胞免疫球蛋白样受体B2（LILRB 2）和它的小鼠直系同源配对免疫球蛋白样受体（PIRB）是几个ANGPTL的受体。LILRB 2和PIRB分别在人和小鼠HSC上表达，并且ANGPTL与这些受体的结合阻止了HSC的快速体内扩增。在小鼠移植急性髓性白血病模型中，PIRB细胞内信号传导的缺陷导致白血病细胞分化增加，表明PIRB支持白血病发展。我们的研究表明，经典的免疫抑制受体在维持正常成体干细胞的干细胞性和支持癌症发展中具有意想不到的功能意义。
How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs)in vitroandin vivo,,,,,,,,,. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered ‘orphan ligands’ because no receptors were identified,,. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supportedex vivoexpansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.
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