PathwayStep809 PathwayStep808 PathwayStep807 PathwayStep806 PathwayStep805 PathwayStep812 PathwayStep813 PathwayStep814 PathwayStep815 PathwayStep810 PathwayStep811 PathwayStep817 PathwayStep816 PathwayStep819 PathwayStep818 PathwayStep847 PathwayStep832 PathwayStep831 PathwayStep830 PathwayStep827 PathwayStep828 PathwayStep829 PathwayStep824 PathwayStep823 PathwayStep826 PathwayStep825 PathwayStep820 PathwayStep822 PathwayStep821 Expression of Interferon-alpha and beta Kinesins Factors involved in megakaryocyte development and platelet production Authored: Akkerman, JW, 2010-10-29 Edited: Jupe, S, 2010-11-12 Megakaryocytes (MKs) give rise to circulating platelets (thrombocytes) through terminal differentiation of MKs which release cytoplasmic fragments as circulating platelets. As MKs mature they undergo endoreduplication (polyploidisation) and expansion of cytoplasmic mass to cell sizes larger than 50-100 microns, and ploidy ranges up to 128 N. As MK's mature, the polyploid nucleus becomes horseshoe-shaped, the cytoplasm expands, and platelet organelles and the demarcation membrane system are amplified. Proplatelet projections form which give rise to de novo circulating platelets (Deutsch & Tomer 2006). <br>The processes of megakaryocytopoiesis and platelet production occur within a complex microenvironment where chemokines, cytokines and adhesive interactions play major roles (Avecilla et al. 2004). Megakaryocytopoiesis is regulated at several levels including proliferation, differentiation and platelet release (Kaushansky 2003). Thrombopoietin (TPO/c-Mpl ligand) is the most potent cytokine stimulating proliferation and maturation of MK progenitors (Kaushansky 2005) but many other growth factors are involved. MK development is controlled by the action of multiple Transcriptin Factors, many MK-specific genes are co-regulated by GATA and friend of GATA (FOG), RUNX1 and ETS proteins. Nuclear factor erythroid 2 (NF-E2) which has an MK-erythroid specific 45-kDa subunit controls terminal MK maturation, proplatelet formation and platelet release (Schulze & Shivdasani 2004). NF-E2 deficient mice have profound thrombocytopenia (Shiraga et al. 1999). c-myb functions with p300 as a negative regulator of thrombopoiesis (Metcalf et al. 2005). During MK maturation, internal membrane systems, granules and organelles are assembled. Cytoplasmic fragmentation requires changes in the MK cytoskeleton and formation of organelles and channels. Individual organelles migrate from the cell body to the proplatelet ends, with approximately 30 percent of organelles/granules in motion at any given time (Richardson et al. 2005). Pubmed10613901 Pubmed12871295 Pubmed14702636 Pubmed15354260 Pubmed15665109 Pubmed16118320 Pubmed16322778 Pubmed16856888 Pubmed17635743 Pubmed17934486 Reactome Database ID Release 43983231 Reactome, http://www.reactome.org ReactomeREACT_24970 Reviewed: Ouwehand, WH, 2010-11-12 RAD51B:RAD51C binds single-stranded DNA Dual-specific AKAPs bind type I and II PKA regulatory subunits RAD51B binds RAD51C IRF1 binds the promoters of Interferon alpha and beta IRF2 binds the promoters of Interferon alpha and beta Mitofusins trans-interact linking mitochondria prior to fusion p53, SIN3A and MYB form a complex Cables1 links CDK2 and WEE1 Cables link CDK5 and ABL1 EHD proteins interact with Rabenosyn-5 Expression of globin genes under control of the beta globin control region DOCKs bind to RhoGEFs Rabenosyn-5 connects Rab5 to VPS-45 Adenylate Kinase 3 is a GTP-AMP phosphotransferase NFE2 binds the beta globin locus control region NFE2 is a heterodimer SH2B proteins bind JAK2 JMJD1C demethylates H3K9 mono- and di-methylation ZFPM proteins bind GATA proteins REST recruits the BHC complex F-actin capping protein binds to the barbed end of elongating F-actin F-actin capping protein is a heterodimer LRRC16A binds F-actin capping protein ITPK1 converts Ins-1,3,4-P3 to Ins-1,3,4,6-P4 ITPK1 converts Ins-1,3,4-P3 to Ins-1,3,4,5-P4 ITPK1 converts Ins-3,4,5,6-P4 to Ins-1,3,4,5,6-P5 HP1 alpha binds Histone H3K9(me)3