Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombopoietin (Tpo) is a cytokine regulating megakaryocyte maturation and platelet formation. We studied Tpo-induced signal transduction, and found that Tpo induces phosphorylation of adapter molecules. Shc and Vav, and of serine/threonine kinases Raf-1 and mitogen-activated protein (MAP) kinases. Further, Tpo induced activation of Ras, MAP kinase kinase, MAP kinase and Pim-1. Taken together with other observations, we concluded that Tpo induces the activation of at least two distinct signaling pathways, a specific Tyk2-JAK2/STAT1-STAT3-STAT5 signaling cascade and a common Shc/Vav/Ras/Raf-1/MAP kinase kinase/MAP kinase signaling cascade.
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PMID:Thrombopoietin induces activation of at least two distinct signaling pathways. 854 84

A variety of environmental stresses, such as osmotic shock, UV radiation, and heat shock, or the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 reportedly induce activation of c-Jun amino-terminal kinases (JNK), which are usually activated by SEK1/MKK4. We report here that the hematopoietic cytokines interleukin-3 (IL-3), erythropoietin (Epo), and thrombopoietin (Tpo), which regulate growth and differentiation of hematopoietic progenitor cells, erythroids, and megakaryocytes/platelets, respectively, also activate a JNK signaling cascade. In-gel kinase assay as well as in vitro kinase assay clearly showed that IL-3, Epo, and Tpo rapidly and transiently activated both JNK1 and JNK2 in IL-3-, Epo-, or Tpo-dependent mouse hematopoietic progenitor cells. However, immunoblot analysis and in vitro kinase assay showed that neither phosphorylation nor activation of SEK1/MKK4 was induced by IL-3, Epo, or Tpo stimulation. Therefore, we concluded that the JNK signaling cascade plays an important role not only in stress responses and proinflammatory cytokine actions but also in hematopoietic cytokine actions and that hematopoietic cytokines may activate the JNKs through a kinase other than SEK1/MKK4, as previously suggested for stress-activated cells.
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PMID:Activation of JNK signaling pathway by erythropoietin, thrombopoietin, and interleukin-3. 910 83

Thrombopoietin (Tpo) is a cytokine which stimulates megakaryocyte maturation. We found that Tpo is constitutively and ubiquitously expressed in all tissues examined, including bone marrow stromal cells, even in thrombocytopenia, thrombosis and steady-state condition in mice. Thus, platelet level in circulation is not regulated by Tpo gene expression. Furthermore, when the purified megakaryocytes were cocultured with the stromal cells, most of the megakaryocytes adhered to the stromal cells and remained unchanged, while free megakaryocytes induced proplatelet formation. Thus the stromal cells in bone marrow secrete Tpo and stimulate megakaryocytopoiesis, but the interaction of megakaryocytes with the stromal cells may suppress platelet formation. Study on signal transduction through Mp1 revealed that Tpo induces activation of JAK2 and Tyk2, which in turn activate STAT1, STAT3 and STAT5. Further, Tpo stimulates transcription factors GATA-1 and NF-E2, which induce differentiation markers, GPIIb/IIIa and Pm-1. In addition, Shc, Vav, Ras, Raf-1, MAPKK, MAPK and Pim-1 are also activated. Thus, Tpo activates a lineage-specific cascade as well as a specific JAK-STAT cascade and a common signaling cascade.
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PMID:Regulation of megakaryocytopoiesis by thrombopoietin and stromal cells. 920 16

The sarcomatoid cells found in cholangiocarcinoma (CC) or hepatocellular carcinoma (HCC) are not well characterized. In this study, a human sarcomatoid CC cell line, ETK-1, was established from a patient, and then morphological and phenotypical characteristics of the ETK-1 cells were evaluated before and after treatment with differentiation-inducing 5-azacytidine (5-azaCR). Phenotypically, the ETK-1 cells appeared immature. Exposure to 5-azaCR induced morphological transformation; a converted cell line, MEK, was successfully established. The MEK cells expressed such hepatocyte-specific proteins as alpha-fetoprotein, albumin, integrin alpha1, and thrombopoietin, but lost such bile duct-specific proteins as integrin alpha3 and integrin beta4. The histopathology of MEK xenografts resembled that of HCC. The ETK-1 cells appeared to be converted into hepatocytes by exposure to 5-azaCR. On the other hand, ETK-1 xenografts were diagnosed as tubular adenocarcinoma, and the tumor cells had a ductal phenotype. This suggests the possibility that ETK-1 cells can differentiate along a biliary epithelial cell lineage. ETK-1 and MEK will be useful in studying hepatocytic differentiation and the transformation from a biliary epithelial cell to a hepatocytic lineage.
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PMID:Hepatocytic phenotypes induced in sarcomatous cholangiocarcinoma cells treated with 5-azacytidine. 925 36

Thrombopoietin (TPO) is the major regulator of both growth and differentiation of megakaryocytes. We previously showed that both functions can be generated by TPO in the megakaryoblastic cell line UT7, in which murine Mpl was introduced, and are independently controlled by distinct regions of the cytoplasmic domain of Mpl. Particularly, residues 71 to 94 of this domain (deleted in the mutant mpl delta3) were found to be required for megakaryocytic maturation but dispensable for proliferation. We show here that TPO-induced differentiation in UT7 cells is tightly dependent on a strong, long-lasting activation of the mitogen-activated protein kinase (MAPK) pathway. Indeed, (i) in UT7-mpl cells, TPO induced a strong activation of extracellular signal-regulated kinases (ERK) which was persistent until at least 4 days in TPO-containing medium; (ii) a specific MAPK kinase (MEK) inhibitor inhibited TPO-induced megakaryocytic gene expression; (iii) the Mpl mutant mpl delta3, which displayed no maturation activity, transduced only a weak and transient ERK activation in UT7 cells; and (iv) TPO-induced megakaryocytic differentiation in UT7-mpl delta3 cells was partially restored by expression of a constitutively activated mutant of MEK. The capacity of TPO to trigger a strong and prolonged MAPK signal depended on the cell in which Mpl was introduced. In BAF3-mpl cells, TPO triggered a weak and transient ERK activation, similar to that induced in UT7-mpl delta3 cells. In these cells, no difference in MAPK activation was found between normal Mpl and mpl delta3. Thus, depending on the cellular context, several distinct regions of the cytoplasmic domain of Mpl and signaling pathways may contribute to generate quantitative variations in MAPK activation.
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PMID:Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. 927 77

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.
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PMID:Thrombopoietin potentiates the protein-kinase-C-mediated activation of mitogen-activated protein kinase/ERK kinases and extracellular signal-regulated kinases in human platelets. 999 Mar 15

Thrombopoietin (TPO) plays a critical role in megakaryocyte proliferation and differentiation. Using various cultured cell lines, several recent studies have implicated the mitogen-activated protein kinase (MAPK) pathway in megakaryocyte differentiation. In the study reported here, we examined the role played by thrombopoietin-induced MAPK activity in a cytokine-dependent cell line (BAF3/Mpl) and in primary murine megakaryocytes. In both systems, extracellular signal-regulated protein kinase (ERK) 1 and 2 MAPK phosphorylation was rapidly induced by TPO stimulation. To identify the Mpl domain responsible for MAPK activation, BAF3 cells expressing truncated forms of the Mpl receptor were studied. Phosphorylation of ERKs did not require elements of the cytoplasmic signaling domain distal to Box 2 and was not dependent on phosphorylation of the adapter protein Shc. ERK activation in murine megakaryocytes was maximal at 10 minutes and was markedly decreased over the subsequent 3 hours. Next, the physiologic consequences of MAPK inhibition were studied. Using the MAPK kinase (MEK) inhibitor, PD 98059, blockade of MAPK activity substantially reduced TPO-dependent proliferation in BAF3/Mpl cells and markedly decreased mean megakaryocyte ploidy in cultures. To exclude an indirect effect of MAPK inhibition on stromal cells in whole bone marrow, CD41(+) cells were selected and then cultured in TPO. The number of polyploid megakaryocytes derived from the CD41-selected cells was also significantly reduced by MEK inhibition, as was their geometric mean ploidy. These studies show an important role for MAPK in TPO-induced endomitosis and underscore the value of primary cells when studying the physiologic effects of signaling pathways.
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PMID:Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. 1043 15

The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate alpha(IIb)beta(3)(+) cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of alpha(IIb)beta(3)(+) cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-kappa B). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in alpha(IIb)beta(3)(+) cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K-AKT axis is differentially involved in TPO- and SDF-1-dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1-regulated adhesion to fibrinogen and vitronectin, and SDF-1-mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses. (Blood. 2000;96:4142-4151)
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PMID:Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis. 1111 Jun 85

The mitogen-activated protein (MAP) kinase cascade is a key regulator of mammalian cell proliferation and differentiation. In this study, we examined the roles of 2 members of the MAP kinase family, extracellular signal-regulated kinase 1 (Erk1) and Erk2, in erythropoietin (EPO)-induced erythroid differentiation and thrombopoietin (TPO)-induced megakaryocytic differentiation. UT-7/GM was used as a model system because this cell line is an erythroid/megakaryocytic bipotent cell line that can be induced to differentiate into the erythroid and megakaryocytic lineages by EPO and TPO, respectively. The kinetics of activation of Erk1 and Erk2 were examined during erythroid and megakaryocytic differentiation of UT-7/GM cells. EPO induced a transient activation of these kinases, peaking after 1 minute of stimulation and then declining quickly almost to the basal level. In contrast, TPO-induced activation of the kinases peaked at 10 minutes and persisted for up to 60 minutes, similar to the activation by granulocyte-macrophage colony-stimulating factor. The percentage of EPO-induced hemoglobin-positive cells was elevated by the addition of PD98059, a specific inhibitor of MEK1 (MAP kinase/ERK kinase 1). In contrast, PD98059 clearly reduced the amount of glycoprotein IIb/IIIa antigens induced by TPO on UT-7/GM cells. Thus, inactivation of Erk1 and Erk2 kinases promoted EPO-induced erythroid differentiation and suppressed TPO-induced megakaryocytic differentiation of UT-7/GM cells. In conclusion, the activation of Erk1 and Erk2 kinases may be a critical event in the determination of cell fate and the differentiation processes of the erythroid and megakaryocytic lineages.
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PMID:A functional role of mitogen-activated protein kinases, erk1 and erk2, in the differentiation of a human leukemia cell line, UT-7/GM: a possible key factor for cell fate determination toward erythroid and megakaryocytic lineages. 1137 59

Thrombopoietin (TPO) plays a critical role not only in proliferation and differentiation of megakaryocytes but also in erythroid differentiation. We have investigated whether the different pathway of mitogen-activated protein kinase (MAPK) after TPO stimulation may discriminate megakaryocyte and erythroid differentiation. In this study, we have used human CD34+ hematopoietic progenitor cells (HPCs) from cord blood (CB) in serum-free liquid culture supplemented with TPO, to compare the respective effects of specific inhibitors of MAPK kinase (MEK) (PD98059) and p38 MAP kinase (p38) (SB203580) on megakaryocyte and erythroid development. PD98059, but not SB203580, significantly suppressed TPO-induced megakaryocyte differentiation when examined by the expression of CD41 and polyploidy assay. In the presence of SB203580, CD34+/CD36+ erythroid progenitors clearly decreased, whereas they increased when cultured with PD98059. These results indicate that activation of extracellular-signal-regulated kinase (ERK) is required for TPO-induced megakaryocyte differentiation and that p38 is required for TPO-induced erythroid differentiation.
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PMID:Requirement of thrombopoietin-induced activation of ERK for megakaryocyte differentiation and of p38 for erythroid differentiation. 1144 31


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