Increased megakaryocytopoiesis in Lyn-deficient mice.
Previous studies in cell lines have shown Lyn kinase to be a negative regulator of thrombopoietin (TPO)-induced proliferation. To further investigate the role of Lyn during megakaryocytopoiesis, Lyn-deficient mice (lyn(-/-)) were analyzed. We observed that lyn(-/-) mice have more bone marrow-derived GPIIB (CD41) and Mpl(+) cells when compared to their wild-type littermates. In addition, colony-forming unit-megakaryocytes (CFU-MK) are increased and TPO-induced expansion of primary marrow cells yielded a greater number of mature megakaryocytes (MKs) with increased nuclear ploidy. Histopathology of bone marrow and spleens from lyn(-/-) mice showed an increase in the number of MKs. Mechanistic studies revealed that TPO stimulation of MKs from lyn(-/-) mice did not affect phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT) 3, STAT5, or MAP kinase kinase (MEK). Lyn-deficient MKs supported greater TPO-mediated phosphorylation and kinase activity of both Erk1/2 (mitogen-activated protein kinase, MAPK) and Akt. In contrast, there was a reduction of tyrosine phosphorylation of the inositol phosphatase, SHIP. This is the first direct evidence using primary MKs from Lyn-deficient mice that confirms our prior data from cell lines that Lyn kinase is a negative regulator of TPO signaling.
Lannutti
B J
BJ
Puget Sound Blood Center, Seattle, WA, USA. brianl@psbc.org
Minear
J
J
Blake
N
N
Drachman
J G
JG
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D008533:Megakaryocytes / Q000166:cytology* / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics; D013922:Thrombocytosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034061:Thrombopoiesis / Q000235:genetics*; D013926:Thrombopoietin / Q000037:antagonists & inhibitors / Q000502:physiology; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D013926:Thrombopoietin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases