Thrombopoietin potentiates activation of human platelets in association with JAK2 and TYK2 phosphorylation

Rodríguez-Liñares, Belén; Watson, Steve P.

doi:10.1042/bj3160093

Cited by 64 publications

(40 citation statements)

References 38 publications

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“…Stimulation and measurements were performed at 37°C. Cytosolic Ca 2ϩ levels were measured as described previously (31). The intracellular Ca 2ϩ concentration was estimated using the equation described by Grynkiewicz et al (32): (R Ϫ R min )/(R max Ϫ R) ϫ K, where K represents the value K d ϫ Sf2/Sb2.…”

Section: Methodsmentioning

confidence: 99%

Tyrosine Phosphorylation of SLP-76 Is Downstream of Syk following Stimulation of the Collagen Receptor in Platelets

Gross¹,

Lee²,

Clements³

et al. 1999

Journal of Biological Chemistry

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112

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have a consensus binding site for the SH2 domain of Vav (DYESP) (2-5) and are heavily tyrosine-phosphorylated following TCR engagement, whereas Tyr 145 , which falls in the sequence DYEPP, is phosphorylated to a lesser extent (6). SLP-76 also contains a central proline-rich region that mediates the association with Grb2 (7) and a carboxyl-terminal SH2 domain that binds to at least two tyrosine-phosphorylated proteins, SLAP-130 (SLP-76-associated phosphoprotein of 130 kDa) (8), a 62-kDa protein, and an uncharacterized serine/threonine kinase after TCR engagement (7). SLP-76 is believed to be an essential adapter protein in T cells. Overexpression of SLP-76 results in an enhancement of TCR-mediated induction of nuclear factor of activated T cell and interleukin-2 promoter activity (3, 5-7, 9, 10). More recently, lack of expression of SLP-76 in Jurkat cells demonstrated that SLP-76 is necessary for tyrosine phosphorylation of phospholipase C-␥ 1 (PLC-␥ 1 ) and activation of the Ras pathway (11). Moreover, SLP-76 is required for normal thymocyte development, since SLP-76 knockout mice lack peripheral T cells (12, 13).The three tyrosine phosphorylation sites, the proline-rich region, and the SH2 domain of SLP-76 have all been shown to be important for the regulation of T cell interleukin 2 production (10). The inducible tyrosine phosphorylation of SLP-76 is mediated by ZAP-70 or Syk in COS cells (9) and rat basophilic leukemia cells (14), respectively. The mechanism by which SLP-76 is phosphorylated by ZAP-70 or Syk is not known.We have previously reported the association of tyrosinephosphorylated SLP-76 with the SH3 domain of Grb2 in platelets in response to stimulation of the low affinity IgG immunoreceptor Fc␥RIIA (15). Increasing evidence suggests that the collagen receptor underlying the major increase in tyrosine phosphorylation in platelets also signals like an immune receptor. The collagen receptor is believed to comprise a multimeric structure, containing the glycoprotein VI (GPVI), and the Fc receptor (FcR) ␥-chain (16 -19). Binding of collagen to GPVI induces tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif in the cytoplasmic tail of FcR ␥-chain (18), leading to tyrosine phosphorylation of Syk and

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Section: Methodsmentioning

confidence: 99%

Tyrosine Phosphorylation of SLP-76 Is Downstream of Syk following Stimulation of the Collagen Receptor in Platelets

Gross¹,

Lee²,

Clements³

et al. 1999

Journal of Biological Chemistry

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112

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“…It has been reported that TPO does not elicit platelet aggregation or the release reaction by itself, but potentiates platelet activation induced by other agonists even in the presence of a cycloxygenase blocker [8,12,14], indicating that TPO enhances platelet activation irrespective of thromboxane A 2 formation. Since we found that TPO directly potentiated the activation of ERKs and MEKs in aspirinized platelets, we speculated that the TPO priming effect on ERKs and MEKs would be implicated in regulation of platelet functions by TPO without involvement of thromboxane A 2 formation.…”

Section: Discussionmentioning

confidence: 99%

“…In PDBu-stimulated platelets, TPO showed a similar dose-dependent effect on ERK2 activation (data not shown). Since TPO potentiates thrombin-induced release of A-granules and densegranules from platelets [11,13,14], we investigated whether the TPO effect on ERK2 was due to the potentiation of the release reaction. TPO potentiated the release reaction of A-granules and dense-granules induced by sub-maximal concentrations (0.025Ϫ 4, 7, 8, 11, 12) for 10 min, and treated with buffer (odd-numbered lanes) or 50 ng/ml TPO (even-numbered lanes) for 3 min before stimulation.…”

Section: Time Courses Of Erk2 and Pkc Activation Induced By Thrombin mentioning

confidence: 99%

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Thrombopoietin potentiates the protein‐kinase‐C‐mediated activation of mitogen‐activated protein kinase/ERK kinases and extracellular signal‐regulated kinases in human platelets

Ezumi

Uchiyama

Takayama

1998

European Journal of Biochemistry

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The thrombopoietin (TPO) receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. We investigated the effect of TPO on the extracellular signal-regulated kinase (ERK) activation pathway in human platelets. TPO by itself did not activate ERK1, ERK2 and protein kinase C (PKC), whereas TPO directly enhanced the PKC-dependent activation of ERKs induced by other agonists including thrombin and phorbol esters, without affecting the PKC activation by those agonists. TPO did not activate the mitogen-activated protein kinase/ERK kinases, MEK1 and MEK2, but activated Raf-1 and directly augmented the PKC-mediated MEK activation, suggesting that TPO primarily potentiates the ERK pathway through regulating MEKs or upstream steps of MEKs including Raf-1. The MEK inhibitor PD098059 failed to affect not only thrombin-induced or phorbol ester-induced aggregation, but also potentiation of aggregation by TPO, denying the primary involvement of ERKs and MEKs in those events. ERKs and MEKs were located mainly in the detergent-soluble/non-cytoskeletal fractions. ERKs but not MEKs were relocated to the cytoskeleton following platelet aggregation and actin polymerization. These data indicate that TPO synergizes with other agonists in the ERK activation pathway of platelets and that this synergy might affect functions of the cytoskeleton possibly regulated by ERKs.Keywords : platelet; thrombopoietin; extracellular signal-regulated kinase ; protein kinase C; signal transduction. Thrombopoietin (TPO) [1Ϫ4], also called the c-Mpl ligand or the megakaryocyte growth and development factor, is the newly identified cytokine that plays a critical role in megakaryocytopoiesis [5]. The TPO receptor, c-Mpl, is expressed in the megakaryocytic lineage from late progenitors to platelets [6]. Others and we have recently reported that TPO induces tyrosine phosphorylation of signaling molecules including Janus tyrosine kinases, JAK2 and Tyk2, Shc, STAT3 and STAT5 in platelets [7Ϫ14], and that TPO does not activate platelets by itself but potentiates other agonists-induced aggregation and release reaction [8, 9, 11Ϫ14].The extracellular signal-regulated kinases (ERKs), ERK1 and ERK2, are the prototypic members of the mitogen-activated protein kinase (MAPK) family and are activated by divergent extracellular stimuli [15Ϫ18]. The ERK signaling pathway through growth factor receptors or cytokine receptors has been well studied. Binding of ligands to receptors leads to activationCorrespondence to H. Takayama, Department of Hematology and Oncology, Clinical Sciences for Pathological Organs, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, Japan 606-8507Fax: ϩ81 75 751 3201. E-mail: hiro@kuhp.kyoto-u.ac.jp Abbreviations. TPO, thrombopoietin; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ ERK kinase; PKC, protein kinase C; GST, glutathione S-transferase ; STA2, 9, 11-epithio-11, 12-methano-thromboxane A2; PMA, phorbol 12-myristate 13-acetate ; ...

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“…18 The same patients however have tendency to a hemorrhagic rather than thrombotic diathesis. Alternative explanations for increased platelet activation include an effect of the JAK2-activating mutation, interaction of abnormal HCT, activated white cells, turbulent flow, or an increase in the known priming effect of thrombopoietin 19 due to elevated thrombopoietin levels. Recent data suggesting that JAK2 affects cMPL cell surface localization and stability 20 may also have implications for the pathogenesis of platelet activation.…”

Section: Platelet Activationmentioning

confidence: 99%

Platelets and Thrombosis in Myeloproliferative Diseases

Harrison¹

2005

Hematology

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The myeloproliferative disorders have been the "poor cousins" in the family of hematological malignancies for some time. Recently this field has advanced considerably with the description of a mutation in the JAK2 kinase detectable in the majority of patients and the publication of two landmark clinical trials-ECLAP and MRC PT1. But although both ECLAP and MRC PT1 inform clinical management and allude to the complexities of thrombosis we still lack fundamental knowledge, and our understanding of thrombosis in these conditions has not paralleled advances in the field of thrombosis and vascular biology. The predominant clinical complications of essential thrombocythemia and polycythemia vera are thrombotic and hemorrhagic; these significantly impact upon prognosis and quality of life. Here the current status of our knowledge is reviewed with specific emphasis upon the role of the platelet in the pathogenesis of thrombosis as well as the impact of recent data from ECLAP and MRC PT1.

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Thrombopoietin potentiates activation of human platelets in association with JAK2 and TYK2 phosphorylation

Cited by 64 publications

References 38 publications

Tyrosine Phosphorylation of SLP-76 Is Downstream of Syk following Stimulation of the Collagen Receptor in Platelets

Tyrosine Phosphorylation of SLP-76 Is Downstream of Syk following Stimulation of the Collagen Receptor in Platelets

Thrombopoietin potentiates the protein‐kinase‐C‐mediated activation of mitogen‐activated protein kinase/ERK kinases and extracellular signal‐regulated kinases in human platelets

Platelets and Thrombosis in Myeloproliferative Diseases

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