Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of interleukin 6 (IL-6)-related cytokines in cardiac homeostasis has been studied extensively; however, little is known about their biological significance in cardiac stem cells. Here we describe that leukemia inhibitory factor (LIF), a member of IL-6-related cytokines, activated STAT3 and ERK1/2 in cardiac Sca-1+ stem cells. LIF stimulation resulted in the induction of endothelial cell-specific genes, including VE-cadherin, Flk-1, and CD31, whereas neither smooth muscle nor cardiac muscle marker genes such as GATA4, GATA6, Nkx-2.5, and calponin were up-regulated. Immunocytochemical examination showed that about 25% of total cells were positively stained with anti-CD31 antibody 14 days after LIF stimulation. Immunofluorescent microscopic analyses identified the Sca-1+ cells that were also positively stained with anti-von Willebrand factor antibody, indicating the differentiating process of Sca-1+ cells into the endothelial cells. IL-6, which did not activate STAT3 and ERK1/2, failed to induce the differentiation of cardiac stem cells into the endothelial cells. In cardiac stem cells, the transduction with dominant negative STAT3 abrogated the LIF-induced endothelial differentiation. And the inhibition of ERK1/2 with the MEK1/2 inhibitor U0126 also prevented the differentiation of Sca-1+ cells into endothelial cells. Thus, both STAT3 and ERK1/2 are required for LIF-mediated endothelial differentiation in cardiac stem cells. Collectively, it is proposed that LIF regulates the commitment of cardiac stem cells into the endothelial cell lineage, contributing to neovascularization in the process of tissue remodeling and/or regeneration.
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PMID:Leukemia inhibitory factor induces endothelial differentiation in cardiac stem cells. 1640 99

Botrocetin (bt)-facilitated binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex on platelets in suspension initiates a signaling cascade that causes alphaIIbbeta3 activation and platelet aggregation. Previous work has demonstrated that bt/VWF-mediated agglutination activates alphaIIbbeta3 and elicits ATP secretion in a thromboxane A2 (TxA2)-dependent manner. The signaling that results in TxA2 production was shown to be initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and PKC. Here, we demonstrate that the signaling elicited by GPIb-mediated agglutination that results in TxA2 production is dependent on Bruton tyrosine kinase (Btk). The results demonstrate that Btk is downstream of Lyn, Syk, SLP-76, and PI3K; upstream of ERK1/2, PLCgamma2, and PKC; and greatly enhances Akt phosphorylation. The relationship(s), if any, between ERK1/2, PLCgamma2, and PKC were not elucidated. The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries. These results demonstrate that the Btk family kinase, Tec, cannot provide the function(s) missing because of the absence of Btk and that Btk is essential for both bt/VWF-mediated agglutination-induced TxA2 production and GPIb-dependent stable arterial thrombus formation in vivo.
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PMID:Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. 1678 3

Aberrant activation of the epidermal growth factor receptor is frequently observed in neoplasia, notably in tumors of epithelial origin. Attempts to treat such tumors with epidermal growth factor receptor antagonists resulted in remarkable success in recent studies. Little is known, however, about the efficacy of this therapy in biliary tract cancer. Protein expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 was assessed in seven human biliary tract cancer cell lines by immunoblotting. In addition, histological sections from 19 patients with extrahepatic cholangiocarcinoma were analyzed for epidermal growth factor receptor, ErbB-2 and vascular endothelial growth factor receptor-2 expression by immunohistochemistry. Moreover, we sequenced the cDNA products representing the entire epidermal growth factor receptor coding region of the seven cell lines, and searched for genomic epidermal growth factor receptor amplifications and polysomy by fluorescence in-situ hybridization. Cell growth inhibition by gefitinib erlotinib and NVP-AEE788 was studied in vitro by automated cell counting. In addition, the anti-tumoral effect of erlotinib and NVP-AEE788 was studied in a chimeric mouse model. The anti-tumoral drug mechanism in this model was assessed by MIB-1 antibody staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end-labelling assay, von Willebrand factor staining, and immunoblotting for p-p42/44 (p-Erk1/2, p-MAPK) and p-AKT. Immunoblotting revealed expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 in all biliary tract cancer cell lines. EGFR was detectable in six of 19 (32%) extrahepatic human cholangiocarcinoma tissue samples, ErbB-2 in 16 of 19 (84%), and vascular endothelial growth factor receptor-2 in nine of 19 (47%). Neither epidermal growth factor receptor mutations nor amplifications or polysomy were found in the seven biliary tract cancer cell lines. Gefitinib, erlotinib and NVP-AEE788 caused a significant growth inhibition in vitro; however, there was a significant difference in efficacy (NVP-AEE788>erlotinib>gefitinib). After 14 days of in-vivo treatment, using the chimeric mouse model, tumors had a significantly reduced volume and mass after NVP-AEE788, but not after erlotinib treatment, as compared with placebo. Reduction of proliferation (signalling via the mitogen-activated protein kinase pathway), induction of apoptosis and inhibition of angiogenesis were the main mechanisms of drug action. No significant reduction of anti-apoptotic AKT phosphorylation, however, occurred, which may be a possible counter mechanism of the tumor. Epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 expression was detectable in biliary tract cancer, and receptor inhibition exerts marked effects on tumor growth in vitro and in vivo, which was strongest for the dual EGFR/ErbB-2 inhibitor NVP-AEE788. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.
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PMID:Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. 1692 28

CCN2 consists of 4 distinct modules that are conserved among various CCN family protein members. From the N-terminus, insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1) and C-terminal cysteine-knot (CT) modules are all aligned tandem therein. The multiple functionality of CCN2 is thought to be enabled by the differential use of these modules when interacting with other molecules. In this study, we independently prepared all 4 purified module proteins of human CCN2, utilizing a secretory production system with Brevibacillus choshinensis and thus evaluated the cell biological effects of such single modules. In human umbilical vascular endothelial cells (HUVECs), VWC, TSP and CT modules, as well as a full-length CCN2, were capable of efficiently activating the ERK signal transduction cascade, whereas IGFBP was not. In contrast, the IGFBP module was found to prominently activate JNK in human chondrocytic HCS-2/8 cells, while the others showed similar effects at lower levels. In addition, ERK1/2 was modestly, but significantly activated by IGFBP and VWC in those cells. No single module, but a mixture of the 4 modules provoked a significant activation of p38 MAPK in HCS-2/8 cells, which was activated by the full-length CCN2. Therefore, the signals emitted by CCN2 can be highly differential, depending upon the cell types, which are thus enabled by the tetramodular structure. Furthermore, the cell biological effects of each module on these cells were also evaluated to clarify the relationship among the modules, the signaling pathways and biological outcomes. Our present results not only demonstrate that single CCN2 modules were potent activators of the intracellular signaling cascade to yield a biological response per se, while also providing new insight into the module-wise structural and functional relationship of a prototypic CCN family member, CCN2.
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PMID:Multiple activation of mitogen-activated protein kinases by purified independent CCN2 modules in vascular endothelial cells and chondrocytes in culture. 1693 82

The peritubular capillary (PTC) network is a component of the tubulointerstitium of the kidney with important roles in renal function and hemodynamics. Bone marrow (BM)-derived cells can contribute to repair of the renal PTC network after ischemic injury. However, the cell fate and the regulation of renal BM-derived cell engraftment in comparison with somatic cells during disease progression are unclear. This study characterized the time course and regulation of PTC endothelial cell injury in adriamycin (ADR)-induced nephropathy in mice, a model of chronic, irreversible, progressive renal disease. Enhanced green fluorescence protein-positive BM cells that coexpressed two endothelial cell markers, von Willebrand factor and CD31, were found to engraft into the PTC of chimeric ADR-injected mice in a time-dependent manner. The number of BM-derived PTC endothelial cells peaked 2 wk after ADR injection, then declined dramatically thereafter. In these mice, apoptosis was evident in BM-derived PTC endothelial cells, and the p38 mitogen-activated protein kinase (MAPK) and TGF-beta1/Smad signaling pathways were activated. Blocking both the p38 MAPK and TGF-beta1/Smad signaling pathways by administration of a p38 MAPK inhibitor (SB203580) and a TGF-beta receptor 1 inhibitor (ALK5I) to ADR-injected mice rescued BM-derived PTC endothelial cells from apoptosis, reduced the loss of PTC, and restored kidney function. Investigation into the signaling pathways that regulate the differentiation and survival of BM-derived cells that engraft into the kidney in the proinflammatory setting of progressive renal disease is vital for the successful development of cell-based therapies to promote renal regeneration and repair.
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PMID:Blockade of p38 mitogen-activated protein kinase and TGF-beta1/Smad signaling pathways rescues bone marrow-derived peritubular capillary endothelial cells in adriamycin-induced nephrosis. 1695 26

Our previous studies have indicated that hypoxia-induced mitogenic factor (HIMF) has angiogenic properties in an in vivo matrigel plug model and HIMF upregulates expression of vascular endothelial growth factor (VEGF) in mouse lungs and cultured lung epithelial cells. However, whether HIMF exerts angiogenic effects through modulating endothelial cell function remains unknown. In this study, mouse aortic rings cultured with recombinant HIMF protein resulted in enhanced vascular sprouting and increased endothelial cell spreading as confirmed by Dil-Ac-LDL uptake, von Willebrand factor and CD31 staining. In cultured mouse endothelial cell line SVEC 4-10, HIMF dose-dependently enhanced cell proliferation, in vitro migration and tubulogenesis, which was not attenuated by SU1498, a VEGFR2/Flk-1 receptor tyrosine kinase inhibitor. Moreover, HIMF stimulation resulted in phosphorylation of Akt, p38 and ERK1/2 kinases in SVEC 4-10 cells. Treatment of mouse aortic rings and SVEC 4-10 cells with LY294002, but not SB203580, PD098059 or U0126, abolished HIMF-induced vascular sprouting and angiogenic responses. In addition, transfection of a dominant-negative mutant of phosphatidylinositol 3-kinase (PI-3K), Deltap85, blocked HIMF-induced phosphorylation of Akt, endothelial activation and tubulogenesis. These results indicate that HIMF enhances angiogenesis by promoting proliferation and migration of endothelial cells via activation of the PI-3K/Akt pathways.
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PMID:Hypoxia-induced mitogenic factor enhances angiogenesis by promoting proliferation and migration of endothelial cells. 1698 54

Recent evidence suggests that bone marrow (BM)-derived cells may integrate into the kidney, giving rise to functional renal cell types, including endothelial and epithelial cells and myofibroblasts. BM-derived cells can contribute to repair of the renal peritubular capillary (PTC) network following acute ischemic injury. However, the cell fate and regulation of BM-derived cells during the progression of chronic renal disease remains unclear. Using chimeric mice transplanted with enhanced green fluorescent protein (EGFP)-expressing BM, we demonstrate that the number of BM-derived myofibroblasts coincided with the development of fibrosis in a mouse adriamycin (ADR)-induced nephrosis model of chronic, progressive renal fibrosis. Four weeks after ADR injection, increased numbers of BM-derived myofibroblasts were observed in the interstitium of ADR-injected mice. Six weeks after ADR injection, more than 30% of renal alpha-smooth muscle actin (+) (alpha-SMA+) interstitial myofibroblasts were derived from the BM. In addition, BM-derived cells were observed to express the endothelial cell marker CD31 and the myofibroblast marker alpha-SMA. Blockade of p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta1/Smad2 signaling was found to protect BM-derived PTC endothelial cells and inhibit the number of BM-derived von Willebrand factor (vWF)(+)/EGFP(+)/alpha-SMA(+) cells, EGFP(+)/alpha-SMA(+) cells, and total alpha-SMA(+) cells in ADR-injected mice. Inhibition of the p38 MAPK and TGF-beta1/Smad signaling pathways enhanced PTC repair by decreasing endothelial-myofibroblast transformation, leading to structural and functional renal recovery and the attenuation of renal interstitial fibrosis. Investigation of the signaling pathways that regulate the differentiation and survival of BM-derived cells in a progressive disease setting is vital for the successful development of cell-based therapies for renal repair.
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PMID:The contribution of bone marrow-derived cells to the development of renal interstitial fibrosis. 1717 67

Isolation of endothelial progenitors from human umbilical cord blood generated great hope in vascular tissue engineering. However, before clinical use, progenitor derived endothelial cells (PDECs) have to be compared with mature endothelial cells (ECs). The aim of this study was to explore the behavior of PDECs exposed to a proinflammatory cytokine (interleukin-1alpha; IL-1alpha) according to the mitogen-activated protein (MAP) kinase and nuclear factor (NF)-kappaB signal transduction pathways as well as procoagulant activity (PCA). CD34(+) mononuclear cells were isolated using magnetic beads, cultured, and compared with human saphenous vein ECs (HSVECs). PDECs express endothelial markers: CD31, VE-cadherin, von Willebrand factor, KDR, and incorporate acetylated low-density lipoprotein (Dil-Ac-LDL). IL-1alpha similarly activates c-Jun N-terminal protein kinase (JNK) and p38 pathways in HSVECs and PDECs, whereas extracellular signal-related kinase (ERK)1/2 phosphorylation is lower in PDECs than in HSVECs. Low ERK1/2 phosphorylation in PDECs was specific to IL-1alpha as vascular endothelial growth factor (VEGF) similarly stimulated ERK1/2 pathway. With respect to inhibitor of NF-kappa B (Ikappa B) degradation, NF-kappa B translocation and phosphorylation, the NF-kappa B pathway is comparable in HSVECs and PDECs after stimulation. PCA and tissue factor level induced by IL-1alpha are lower in PDECs than in HSVECs. Thus, our data show that PDECs display the characteristics of functional mature ECs under IL-1alpha stimulation. However, we observed significant differences between PDECs and HSVECs related to both ERK1/2 pathway activation and tissue factor production.
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PMID:Signal transduction and procoagulant state of human cord blood--progenitor-derived endothelial cells after interleukin-1alpha stimulation. 1757 11

The involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase-1 (JNK1) has never been investigated in hemostasis and thrombosis. Using two JNK inhibitors (SP600125 and 6o), we have demonstrated that JNK1 is involved in collagen-induced platelet aggregation dependent on ADP. In these conditions, JNK1 activation requires the coordinated signaling pathways of collagen receptors (alpha2beta1 and glycoprotein (GP)VI) and ADP. In contrast, JNK1 is not required for platelet adhesion on a collagen matrix in static or blood flow conditions (300-1500 s(-1)) involving collagen receptors (alpha2beta1 and GPVI). Importantly, at 1500 s(-1), JNK1 acts on thrombus formation on a collagen matrix dependent on GPIb-von Willebrand factor (vWF) interaction but not ADP receptor activation. This is confirmed by the involvement of JNK1 in shear-induced platelet aggregation at 4000 s(-1). We also provide evidence during rolling and adhesion of platelets to vWF that platelet GPIb-vWF interaction triggers alphaIIbbeta3 activation in a JNK1-dependent manner. This was confirmed with a Glanzmann thrombastenic patient lacking alphaIIbbeta3. Finally, in vivo, JNK1 is involved in arterial but not in venular thrombosis in mice. Overall, our in vitro studies define a new role of JNK1 in thrombus formation in flowing blood that is relevant to thrombus development in vivo.
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PMID:Involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase 1 in thrombus formation. 1778 64

Multi-potent adult progenitor cells (MAPCs) differentiate into endothelial cells (ECs) in the presence of vascular endothelial growth factor (VEGF). The mechanism(s) of VEGF-induced differentiation of MAPCs to ECs are not yet known. We, therefore, examined the role of mitogen-activated protein kinase/extracellular signal-regulated kinase (p42/44-MAPK/ERK1/2) signalling in endothelial differentiation from bone marrow stem cells. We observed that VEGF stimulation of MAPCs for 14 days results in a significant expression of endothelial-specific gene and/or proteins including von Willebrand factor (vWF), vascular endothelial-cadherin (VE-cadherin), VEGF receptor-2 (VEGFR2), and CD31. Up-regulation of EC-specific markers was accompanied by a cobblestone morphology, expression of endothelial nitric oxide synthase (eNOS), and Dil-Ac-LDL uptake, typical for EC morphology and function. VEGF induced a sustained activation of p42 MAPK/ERK, but not that of p44 MAPK/ERK during the course of MAPCs differentiation in a time-dependent manner up to 14 days. VEGF-induced activation of p42 MAPK/ERK also led to the nuclear translocation of MAPK/ERK1/2. Incubation of MAPCs with MAPK/ERK1/2 phosphorylation inhibitor PD98059 blocked the sustained VEGF-induced MAPK/ERK1/2 phosphorylation as well as its nuclear translocation in the differentiating MAPCs. Inhibition of MAPK/ERK1/2 phosphorylation by PD98059 also blocked the expression of EC-specific genes in these cells and their differentiation to ECs. These data suggest that VEGF induces MAPC differentiation into EC via a. MAPK/ERK1/2 signalling pathway-mediated mechanism in vitro.
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PMID:MAPK/ERK signalling mediates VEGF-induced bone marrow stem cell differentiation into endothelial cell. 1826 67


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