title: Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals.
abstract: 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.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864; zhuhecrane@shsmu.edu.cn gfeng@ucsd.edu.
authors.forename: Helen He
authors.initials: HH
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864;
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
authors.forename: Kaiqing
authors.initials: K
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
authors.forename: Zhongzhong
authors.initials: Z
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
authors.forename: Jufang
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Lifan
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864;
authors.forename: Kaihong
authors.initials: K
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Wei-Qiang
authors.initials: WQ
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864; zhuhecrane@shsmu.edu.cn gfeng@ucsd.edu.
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D000740:Anemia / Q000209:etiology / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004912:Erythrocytes / Q000502:physiology; D004920:Erythropoiesis / Q000502:physiology*; D005838:Genotype; D006652:Histological Techniques; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D038042:Myelopoiesis / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D017931:DNA Primers; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Pten; Shp2; anemia; erythropoiesis; myeloproliferative neoplasm