Abstract
The stem cell factor (SCF)/Kit system has served as a classic model in deciphering molecular signaling events in the hematopoietic compartment, and Kit expression is a most critical marker for hematopoietic stem cells (HSCs) and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. Herein we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit and other RTKs, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling axis. Inducible ablation of PTPN11/Shp2 resulted in severe cytopenia in BM, spleen, and peripheral blood in mice. Shp2 removal suppressed the functional pool of HSCs/progenitors, and Shp2-deficient HSCs failed to reconstitute lethally irradiated recipients because of defects in homing, self-renewal, and survival. We show that Shp2 regulates coordinately multiple signals involving up-regulation of Kit expression via Gata2. Therefore, this study reveals a critical role of Shp2 in maintenance of a functional HSC/progenitor pool in adult mammals, at least in part through a kinase-phosphatase-kinase cascade.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult Stem Cells / cytology
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Adult Stem Cells / metabolism
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Anemia, Aplastic
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Animals
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Apoptosis
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Base Sequence
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Bone Marrow Diseases
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Bone Marrow Failure Disorders
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Bone Marrow Transplantation
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Cell Proliferation
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Down-Regulation
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism
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Feedback, Physiological
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GATA2 Transcription Factor / genetics
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GATA2 Transcription Factor / metabolism
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Hematopoiesis
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / metabolism*
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Hemoglobinuria, Paroxysmal / etiology
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Leukopenia / etiology
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Mice
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Mice, Knockout
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism*
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RNA, Small Interfering / genetics
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Signal Transduction
Substances
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GATA2 Transcription Factor
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Gata2 protein, mouse
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RNA, Small Interfering
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Proto-Oncogene Proteins c-kit
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Ptpn11 protein, mouse