Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals
Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals
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DOI：
10.1073/pnas.1507599112
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发表时间：
2015-10
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通讯作者：
H. Zhu;Xiaolin Luo;Kaiqing Zhang;Jian Cui;Huifang Zhao;Z. Ji;Zhicheng Zhou;Jufang Yao;Lifan Zeng;Kaihong Ji;Wei-Qiang Gao;Zhon-Yin Zhang;G. Feng
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文献类型：
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作者：
H. Zhu;Xiaolin Luo;Kaiqing Zhang;Jian Cui;Huifang Zhao;Z. Ji;Zhicheng Zhou;Jufang Yao;Lifan Zeng;Kaihong Ji;Wei-Qiang Gao;Zhon-Yin Zhang;G. Feng
意义 尽管磷酸酶和张力蛋白同源物 (Pten) 或含有 SH2 的酪氨酸磷酸酶 (Shp2) 在细胞信号传导中的功能受到广泛关注，但它们的调控途径如何交织在一起尚未得到研究。通过创建血细胞中两个基因均被删除的复合突变小鼠系，我们发现 Pten 和 Shp2 在骨髓生成中可以拮抗作用，而在红细胞生成中可以协同作用。一致地，Shp2 的药理抑制抑制了 Pten 缺失引起的骨髓增殖性肿瘤，但引起了严重贫血。这些数据解释了为什么一些针对特定途径的药物可以抑制一种致病过程，但却引发另一种致病过程。先前的数据表明，磷酸酶和张力蛋白同源物 (Pten) 在骨髓细胞生成和白血病发生中发挥负作用，而含有 SH2 的酪氨酸磷酸酶 (Shp2)/Ptpn11 则具有正作用。在此，我们证明消除Shp2确实抑制了Pten缺失的骨髓增殖作用，表明这两种酶调节的途径之间具有直接相反的功能。令人惊讶的是，Shp2 和 Pten 双敲除小鼠患有致命性贫血，这种表型揭示了 Pten 和 Shp2 在红细胞生成中以前未被认识到的协同作用。致命性贫血是由祖细胞分化失常和红细胞寿命缩短共同引起的。一致的是，用特定的 Shp2 抑制剂治疗 Pten 缺陷小鼠可抑制骨髓增殖性肿瘤，同时引起贫血。这些结果确定了 Pten 和 Shp2 在促进红细胞生成方面的协同作用，同时在骨髓增殖性肿瘤的发展中发挥拮抗作用。这项研究阐明了血细胞谱系中细胞类型特异性信号串扰，并将指导精准医学时代更好地设计针对白血病和其他类型癌症的药物。
Significance Despite the extensive attentions paid to phosphatase and tensin homolog (Pten) or SH2-containing tyrosine phosphatase (Shp2) functions in cell signaling, how their regulated pathways are intertwined has never been investigated. By creating a compound mutant mouse line with both genes deleted in blood cells, we have found that Pten and Shp2 can work antagonistically in myelopoiesis, while acting cooperatively in erythropoiesis. Consistently, pharmacological inhibition of Shp2 suppressed myeloproliferative neoplasm induced by Pten loss but induced severe anemia. These data explain why some pharmaceuticals designed to target a specific pathway can suppress one pathogenic process but trigger another. Previous data suggested a negative role of phosphatase and tensin homolog (Pten) and a positive function of SH2-containing tyrosine phosphatase (Shp2)/Ptpn11 in myelopoiesis and leukemogenesis. Herein we demonstrate that ablating Shp2 indeed suppressed the myeloproliferative effect of Pten loss, indicating directly opposing functions between pathways regulated by these two enzymes. Surprisingly, the Shp2 and Pten double-knockout mice suffered lethal anemia, a phenotype that reveals previously unappreciated cooperative roles of Pten and Shp2 in erythropoiesis. The lethal anemia was caused collectively by skewed progenitor differentiation and shortened erythrocyte lifespan. Consistently, treatment of Pten-deficient mice with a specific Shp2 inhibitor suppressed myeloproliferative neoplasm while causing anemia. These results identify concerted actions of Pten and Shp2 in promoting erythropoiesis, while acting antagonistically in myeloproliferative neoplasm development. This study illustrates cell type-specific signal cross-talk in blood cell lineages, and will guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.