Kit-Shp2-Kit signaling acts to maintain a functional hematopoietic stem and progenitor cell pool

Blood. 2011 May 19;117(20):5350-61. doi: 10.1182/blood-2011-01-333476. Epub 2011 Mar 30.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / metabolism
  • Anemia, Aplastic
  • Animals
  • Apoptosis
  • Base Sequence
  • Bone Marrow Diseases
  • Bone Marrow Failure Disorders
  • Bone Marrow Transplantation
  • Cell Proliferation
  • Down-Regulation
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Feedback, Physiological
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Hemoglobinuria, Paroxysmal / etiology
  • Leukopenia / etiology
  • Mice
  • Mice, Knockout
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction

Substances

  • GATA2 Transcription Factor
  • Gata2 protein, mouse
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-kit
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse