Essential role for Ptpn11 in survival of hematopoietic stem and progenitor cells

被引:80
作者
Chan, Gordon [1 ,2 ,3 ,4 ]
Cheung, Laurene S. [5 ,6 ]
Yang, Wentian [2 ,3 ]
Milyavsky, Michael [1 ,4 ,7 ]
Sanders, Ashley D. [1 ,4 ]
Gu, Shengqing [1 ,4 ,8 ]
Hong, Wan Xing [5 ,6 ]
Liu, Aurora X. [1 ,4 ]
Wang, Xiaonan [1 ,4 ,8 ]
Barbara, Mary [9 ,10 ]
Sharma, Tarun [1 ,4 ]
Gavin, Joehleen [5 ,6 ]
Kutok, Jeffery L. [11 ]
Iscove, Norman N. [9 ,10 ]
Shannon, Kevin M. [5 ,6 ]
Dick, John E. [1 ,4 ,7 ]
Neel, Benjamin G. [1 ,2 ,3 ,4 ,8 ]
Braun, Benjamin S. [5 ,6 ]
机构
[1] Ontario Canc Inst, Campbell Family Canc Res Inst, Toronto, ON M5G 1L7, Canada
[2] Beth Israel Deaconess Med Ctr, Canc Biol Program, Boston, MA 02215 USA
[3] Harvard Univ, Sch Med, Boston, MA USA
[4] Princess Margaret Hosp, Univ Hlth Network, Toronto, ON M4X 1K9, Canada
[5] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[6] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA
[7] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
[8] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[9] Univ Toronto, Dept Immunol, Toronto, ON, Canada
[10] Univ Toronto, McEwen Ctr Regenerat Med, Toronto, ON, Canada
[11] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
SHP-2 TYROSINE PHOSPHATASE; CAENORHABDITIS-ELEGANS; SIGNAL-TRANSDUCTION; ADAPTER PROTEIN; NOONAN-SYNDROME; SELF-RENEWAL; APOPTOSIS; MICE; DIFFERENTIATION; PATHWAY;
D O I
10.1182/blood-2010-11-319517
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Blood. 2011;117(16):4253-4261)
引用
收藏
页码:4253 / 4261
页数:9
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