Thrombopoietin induces tyrosine phosphor-ylation and activation of the Janus kinase, JAK2

Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA.
Blood (Impact Factor: 10.45). 07/1995; 85(12):3444-51.
Source: PubMed


Thrombopoietin (TPO) is a recently characterized growth and differentiation factor for megakaryocytes and platelets that exerts its effects via the receptor, c-MpI. This receptor is a member of the hematopoietin receptor superfamily and is essential for megakaryocyte maturation; however, the molecular mechanisms of TPO and c-MpI action have not been elucidated. Recently, the Janus kinases have emerged as important elements in signaling via this family of receptors. In this report, we show that, in the M07e megakaryocytic cell line, which expresses c-MpI and proliferates in response to TPO, TPO induces phosphorylation of a number of substrates between 80 and 140 kD. Specifically, we show that stimulation with TPO induces the rapid tyrosine phosphorylation of a 130-kD protein that we identify as the Janus kinase, JAK2. However, no detectable tyrosine phosphorylation of JAK1, JAK3, or TYK2 was observed. TPO also induced activation of JAK2 phosphotransferase activity in vitro. Taken together, these data indicate that JAK2 likely plays a key role in TPO-mediated signal transduction.

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Available from: Dan Longo, Aug 12, 2014
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    • "Thrombopoietin (Tpo) is the principal cytokine regulator of megakaryopoiesis, through binding to its cognate receptor Mpl. Tpo activates the Jak2 and Tyk2 tyrosine kinases [1] as well as the Stat3 and Stat5 transcription factors [2,3,4]. The importance of Tpo, its receptor and proximal signaling pathways in platelet function is illustrated by the discovery of gain-of-function mutations in Tpo [5], Mpl [6,7] and Jak2 [8,9,10,11] that all result in Essential Thrombocythemia (ET). "
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    ABSTRACT: Utilizing ENU mutagenesis, we identified a mutant mouse with elevated platelets. Genetic mapping localized the mutation to an interval on chromosome 19 that encodes the Jak2 tyrosine kinase. We identified a A3056T mutation resulting in a premature stop codon within exon 19 of Jak2 (Jak2 (K915X) ), resulting in a protein truncation and functionally inactive enzyme. This novel platelet phenotype was also observed in mice bearing a hemizygous targeted disruption of the Jak2 locus (Jak2 (+/-) ). Timed pregnancy experiments revealed that Jak2 (K915X/K915X) and Jak2 (-/-) displayed embryonic lethality; however, Jak2 (K915X/K915X) embryos were viable an additional two days compared to Jak2 (-/-) embryos. Our data suggest that perturbing JAK2 activation may have unexpected consequences in elevation of platelet number and correspondingly, important implications for treatment of hematological disorders with constitutive Jak2 activity.
    PLoS ONE 09/2013; 8(9):e75472. DOI:10.1371/journal.pone.0075472 · 3.23 Impact Factor
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    • "Based on the crystallographic EPO receptor study and its analogy to the TPO receptor have led to the postulation that TPO initiates the signal transduction by binding to the c-Mpl at the distal part, which in turn a homodimer of c-Mpl becomes active [15]. Consequently, Janus kinase 2 (JAK2) can phosphorylate tyrosine residues within the receptor itself which at least two tyrosine residues, Tyr625 and Tyr630, are phosphorylated on c-Mpl [15, 122], thereby stimulating the downstream cascade STATs, PI3K, the mitogen-activated protein kinases (MAPKs), and extracellular signal regulated kinases-1 and -2 (Figure 5) [123, 124]. c-Mpl/TPO signaling involved in postnatal steady-state HSC maintenance and cell-cycle progression at the endosteal surface [125, 126]. "
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    ABSTRACT: Hematopoietic stem cells (HSCs) play a key role in hematopoietic system that functions mainly in homeostasis and immune response. HSCs transplantation has been applied for the treatment of several diseases. However, HSCs persist in the small quantity within the body, mostly in the quiescent state. Understanding the basic knowledge of HSCs is useful for stem cell biology research and therapeutic medicine development. Thus, this paper emphasizes on HSC origin, source, development, the niche, and signaling pathways which support HSC maintenance and balance between self-renewal and proliferation which will be useful for the advancement of HSC expansion and transplantation in the future.
    07/2012; 2012:270425. DOI:10.1155/2012/270425
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    Progress in hemostasis and thrombosis 02/1984; 7:111-50.
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