SH2-inositol phosphatase 1 negatively influences early megakaryocyte progenitors.
BACKGROUND
The SH2-containing-5'inositol phosphatase-1 (SHIP) influences signals downstream of cytokine/chemokine receptors that play a role in megakaryocytopoiesis, including thrombopoietin, stromal-cell-derived-Factor-1/CXCL-12 and interleukin-3. We hypothesize that SHIP might control megakaryocytopoiesis through effects on proliferation of megakaryocyte progenitors (MKP) and megakaryocytes (MK).


RESULTS
Herein, we report the megakaryocytic phenotype and MK functional assays of hematopoietic organs of two strains of SHIP deficient mice with deletion of the SHIP promoter/first exon or the inositol phosphatase domain. Both SHIP deficient strains exhibit a profound increase in MKP numbers in bone marrow (BM), spleen and blood as analyzed by flow cytometry (Lin(-)c-Kit+CD41+) and functional assays (CFU-MK). SHIP deficient MKP display increased phosphorylation of Signal Transducers and Activators of Transcription 3 (STAT-3), protein kinase B (PKB/AKT) and extracellular signal-regulated kinases (ERKs). Despite increased MKP content, total body number of mature MK (Lin(-)c-kit(-)CD41+) are not significantly changed as SHIP deficient BM contains reduced MK while spleen MK numbers are increased. Reduction of CXCR-4 expression in SHIP deficient MK may influence MK localization to the spleen instead of the BM. Endomitosis, process involved in MK maturation, was preserved in SHIP deficient MK. Circulating platelets and red blood cells are also reduced in SHIP deficient mice.


CONCLUSIONS
SHIP may play an important role in regulation of essential signaling pathways that control early megakaryocytopoiesis in vivo.
Perez
Lia E
LE
Blood and Marrow Transplantation Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, Florida, USA.
Desponts
Caroline
C
Parquet
Nancy
N
Kerr
William G
WG
D000818:Animals; D001773:Blood Cells / Q000378:metabolism / Q000502:physiology; D001853:Bone Marrow / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000502:physiology; D034061:Thrombopoiesis / Q000235:genetics
C514936:CXCR4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D019718:Receptors, CXCR4; D011494:Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases