Abstract
Megakaryocytes release platelets into the bloodstream by elongating proplatelets. In this study, we showed that human megakaryocytes constitutively release Transforming Growth Factor β1 and express its receptors. Importantly, Transforming Growth Factor β1 downstream signaling, through SMAD2/3 phosphorylation, was shown to be active in megakaryocytes extending proplatelets, indicating a type of autocrine stimulation on megakaryocyte development. Furthermore, inactivation of Transforming Growth Factor β1 signaling, by the receptor inhibitors SB431542 and Stemolecule ALK5 inhibitor, determined a significant decrease in proplatelet formation. Recent studies indicated a crucial role of Transforming Growth Factor β1 in the pathogenesis of primary myelofibrosis. We demonstrated that primary myelofibrosis-derived megakaryocytes expressed increased levels of bioactive Transforming Growth Factor β1; however, higher levels of released Transforming Growth Factor β1 did not lead to enhanced activation of downstream pathways. Overall, these data propose Transforming Growth Factor β1 as a new element in the autocrine regulation of proplatelet formation in vitro. Despite the increase in Transforming Growth Factor β1 this mechanism seems to be preserved in primary myelofibrosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Autocrine Communication*
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Benzamides / pharmacology
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Blood Platelets / cytology
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Blood Platelets / metabolism
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Blotting, Western
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Cells, Cultured
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Dioxoles / pharmacology
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Gene Expression
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Humans
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Megakaryocytes / cytology
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Megakaryocytes / metabolism*
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Phosphorylation
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Primary Myelofibrosis / blood
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Primary Myelofibrosis / genetics*
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Primary Myelofibrosis / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / metabolism
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Transforming Growth Factor beta1 / genetics*
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Transforming Growth Factor beta1 / metabolism
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Benzamides
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Dioxoles
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Receptors, Transforming Growth Factor beta
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SMAD2 protein, human
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Smad2 Protein
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Smad3 Protein
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Transforming Growth Factor beta1
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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TGFBR1 protein, human