Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals


Zhu Helen He,Luo Xiaolin,Zhang Kaiqing,Cui Jian,Zhao Huifang,Ji Zhongzhong,Zhou Zhicheng,Yao Jufang,Zeng Lifan,Ji Kaihong,Gao Wei-Qiang,Zhang Zhong-Yin,Feng Gen-Sheng


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.


HHS | National Institutes of Health

Science and Technology Commission of Shanghai Municipality

Shanghai Municipal Education Commission

Shanghai Institutions of Higher Learning


Proceedings of the National Academy of Sciences



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