title: Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells.
abstract: Src homology 2 domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is a member of the nonreceptor protein-tyrosine phosphatase family, and functions in cell survival, proliferation, migration, and differentiation in many tissues. Here we report that loss of Ptpn11 in murine hematopoietic cells leads to bone marrow aplasia and lethality. Mutant mice show rapid loss of hematopoietic stem cells (HSCs) and immature progenitors of all hematopoietic lineages in a gene dosage-dependent and cell-autonomous manner. Ptpn11-deficient HSCs and progenitors undergo apoptosis concomitant with increased Noxa expression. Mutant HSCs/progenitors also show defective Erk and Akt activation in response to stem cell factor and diminished thrombopoietin-evoked Erk activation. Activated Kras alleviates the Ptpn11 requirement for colony formation by progenitors and cytokine/growth factor responsiveness of HSCs, indicating that Ras is functionally downstream of Shp2 in these cells. Thus, Shp2 plays a critical role in controlling the survival and maintenance of HSCs and immature progenitors in vivo.
authors.affiliation: Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. gordon.chan@uhnresearch.ca
authors.forename: Gordon
authors.initials: G
authors.lastname: Chan
authors.forename: Laurene S
authors.initials: LS
authors.lastname: Cheung
authors.forename: Wentian
authors.initials: W
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Milyavsky
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Sanders
authors.forename: Shengqing
authors.initials: S
authors.lastname: Gu
authors.forename: Wan Xing
authors.initials: WX
authors.lastname: Hong
authors.forename: Aurora X
authors.initials: AX
authors.lastname: Liu
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Barbara
authors.forename: Tarun
authors.initials: T
authors.lastname: Sharma
authors.forename: Joehleen
authors.initials: J
authors.lastname: Gavin
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Norman N
authors.initials: NN
authors.lastname: Iscove
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Braun
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D002453:Cell Cycle; D016923:Cell Death; D004843:Epistasis, Genetic; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)