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.
journal_name
Bloodjournal_title
Bloodauthors
Chan G,Cheung LS,Yang W,Milyavsky M,Sanders AD,Gu S,Hong WX,Liu AX,Wang X,Barbara M,Sharma T,Gavin J,Kutok JL,Iscove NN,Shannon KM,Dick JE,Neel BG,Braun BSdoi
10.1182/blood-2010-11-319517subject
Has Abstractpub_date
2011-04-21 00:00:00pages
4253-61issue
16eissn
0006-4971issn
1528-0020pii
blood-2010-11-319517journal_volume
117pub_type
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