SH(2)-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). METHODOLOGY AND PRINCIPAL FINDINGS: 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/SIGNIFICANCE: SHIP may play an important role in regulation of essential signaling pathways that control early megakaryocytopoiesis in vivo.