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

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.