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)

Adenosine promotes adrenal steroidogenesis in vitro and in vivo. However, the underlying signaling mechanisms of this event and the function of the adenosine receptor subtypes in adrenal cells remain to be elucidated. Expression of A1, A2A, A2B, and A3 adenosine receptor mRNA in rat adrenal cells was shown by reverse transcription-polymerase chain reaction. Adenosine increased corticosterone production in a time- and dose-dependent manner, and this adenosine effect was mediated by the A2 adenosine receptors, since the antagonists specific for the A2A and A2B adenosine receptors, and specific silencing the A2A adenosine receptor expression with small interfering RNA significantly blocked the adenosine-induced steroidogenesis. Using pharmacological approaches, we further demonstrated that Janus kinase 2 was the downstream molecule next to the A2A and A2B adenosine receptors. Inhibition of Janus kinase 2 prevented the adenosine-induced steroidogenesis and phosphorylation of mitogen-activated protein kinase kinase 1/2 and extracellular signal-regulated kinase 1/2, demonstrating that Janus kinase 2 was the upstream effector of the mitogen-activated protein kinase kinase pathway. Pretreatment with A2 adenosine receptor, Janus kinase 2, or mitogen-activated protein kinase kinase inhibitors significantly decreased the adenosine-induced phosphorylation of 3',5'-cyclic adenosine monophosphate responsive element binding protein. In conclusion, these data show that adenosine-stimulated steroidogenesis is mediated via the A2A and A2B adenosine receptors, activation of which triggers the Janus kinase 2-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase cascade and 3',5'-cyclic adenosine monophosphate responsive element binding protein phosphorylation. Based on its stimulatory effect on glucocorticoid production, adenosine is a potential candidate as anti-inflammatory agent.
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PMID:Adenosine-stimulated adrenal steroidogenesis involves the adenosine A2A and A2B receptors and the Janus kinase 2-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase signaling pathway. 1858 95

Interleukin (IL)-17 is a pro-inflammatory cytokine produced by recently described T helper type 17 (Th17) cells, which have critical role in immunity to extracellular bacteria and the pathogenesis of several autoimmune disorders. IL-6 and transforming growth factor (TGF)-beta are crucial for the generation of Th17 cells in mice, while the production of IL-17 is supported by various cytokines, including IL-23, IL-1beta, IL-21, IL-15 and tumour necrosis factor (TNF)-alpha. In this study, the influence of a multifunctional cytokine, macrophage migration inhibitory factor (MIF), on IL-17 production in mice was investigated. Treatment of lymph node cells (LNCs) with recombinant MIF up-regulated mitogen-stimulated IL-17 expression and secretion. Additionally, LNCs from MIF knockout mice (mif(-/-)) had severely impaired production of IL-17, as well as of IL-1beta, IL-6, IL-23 and TGF-beta. When stimulated with recombinant IL-1beta, IL-23 or TNF-alpha, mitogen-triggered mif(-/-) LNCs were fully able to achieve the IL-17 production seen in wild-type (WT) LNCs, while the addition of IL-6 and TGF-beta had no effect. Finally, after injection of mice with complete Freund's adjuvant, secretion of IL-17 as well as the number of IL-17-positive cells was significantly lower in the draining lymph nodes of mif(-/-) mice in comparison with WT mice. The effect of MIF on IL-17 production was dependent on p38, extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/STAT3), and not on nuclear factor (NF)-kappaB and nuclear factor of activated T cells (NFAT) signalling. Bearing in mind the contribution of MIF and IL-17 to the pathology of inflammatory and autoimmune disorders, from the results presented here it seems plausible that targeting MIF biological activity could be a valid therapeutic approach for the treatment of such diseases.
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PMID:Macrophage migration inhibitory factor stimulates interleukin-17 expression and production in lymph node cells. 1862 29

Leptin controls body weight by activating the long form of the leptin receptor (LEPRb). Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. Surprisingly, here we show that JAK2 is not required for leptin stimulation of STAT3 phosphorylation. Leptin time- and dose-dependently stimulated tyrosine phosphorylation of STAT3 in both human and mouse JAK2-null cells. Leptin also increased the viability of JAK2-null cells. Overexpression of c-Src or Fyn, two Src family members, promoted STAT3 phosphorylation, whereas inhibition of the endogenous Src family members by either pharmacological inhibitors or dominant negative Src(K298M) decreased the ability of leptin to stimulate the phosphorylation of STAT3 and ERK1/2. Leptin also stimulated tyrosine phosphorylation of kinase-inactive JAK2(K882E) in JAK2-null cells. Overexpression of JAK2(K882E) enhanced the ability of leptin to stimulate STAT3 phosphorylation in JAK2-null cells. Tyr1138 in LEPRb was required for leptin-stimulated phosphorylation of STAT3 but not JAK2(K882E). These data suggest that leptin stimulates non-JAK2 tyrosine kinase(s), including the Src family members, which phosphorylate JAK2, STAT3, and other molecules downstream of LEPRb. JAK2 mediates leptin signaling by both phosphorylating its substrates and forming a signaling complex as a scaffolding/adaptor protein. The non-JAK2 kinase(s) and JAK2 may act coordinately and synergistically to mediate leptin response.
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PMID:Leptin stimulates both JAK2-dependent and JAK2-independent signaling pathways. 1871 5

Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in cardiomyocytes from adult rats fed low- and high-fat diets for 12 weeks. Cardiomyocyte contractile and intracellular Ca(2+) properties were examined including peak shortening, duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dl/dt), Fura-2-fluorescence intensity change (DeltaFFI), and intracellular Ca(2+) decay rate (tau). Expression of the leptin receptor (Ob-R) was evaluated by western blot analysis. High-fat diet increased systolic blood pressure and plasma leptin levels. PS and +/-dl/dt were depressed whereas TPS and TR(90) were prolonged after high-fat diet feeding. Leptin elicited a concentration-dependent (0-1,000 nmol/l) inhibition of PS, +/-dl/dt, and DeltaFFI in low-fat but not high-fat diet-fed rat cardiomyocytes without affecting TPS and TR(90). The Janus kinase 2 (JAK2) inhibitor AG490, the mitogen-activated protein kinase (MAPK) inhibitor SB203580, and the nitric oxide synthase (NOS) inhibitor L-NAME abrogated leptin-induced cardiomyocyte contractile response in low-fat diet group without affecting the high-fat diet group. High-fat diet significantly downregulated cardiac expression of Ob-R. Elevation of extracellular Ca(2+) concentration nullified obesity-induced cardiomyocyte mechanical dysfunction and leptin-induced depression in PS. These data indicate presence of cardiac leptin resistance in diet-induced obesity possibly associated with impaired leptin receptor signaling.
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PMID:High-fat diet-induced obesity leads to resistance to leptin-induced cardiomyocyte contractile response. 1871 78

Reactive oxygen species (ROS) have been implicated in vascular smooth muscle cell (VSMC) apoptosis, a hallmark of advanced atherosclerotic lesions. Transient oxidation and inactivation of protein-tyrosine phosphatases play a critical role in cellular response to ROS production. However, the function of leukocyte antigen-related (LAR) protein-tyrosine phosphatase in ROS signaling is not known. To determine the expression of LAR in ROS-induced apoptosis, we investigated hydrogen peroxide-induced cell death and signaling in aortic VSMCs from wild-type and LAR(-/-) mice. Histone-associated DNA fragmentation and caspase-3/7 activity were significantly enhanced, mitochondrial membrane integrity was compromised, and cell viability was significantly decreased following H(2)O(2) treatment in LAR(-/-) VSMCs compared with wild-type cells. Stronger and sustained increase in autophosphorylation and activity of Fyn, an Src family tyrosine kinase, was observed in LAR(-/-) cells compared with wild-type cells following H(2)O(2) treatment. LAR binds to activated Fyn in H(2)O(2)-treated VSMCs, and recombinant LAR dephosphorylates phosphorylated-Fyn in vitro. In addition, LAR deficiency enhanced H(2)O(2)-induced phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen-activated protein kinase (MAPK). PP2, a Fyn-specific inhibitor, blocked JAK2, STAT3, and p38 MAPK activation and significantly attenuated apoptosis induced by H(2)O(2). AG490, a JAK2-specific inhibitor, significantly attenuated H(2)O(2)-induced apoptosis, and blocked H(2)O(2)-induced activation of STAT3, but not p38 MAPK in both wild-type and LAR(-/-) VSMCs. Attenuation of Fyn expression by short hairpin RNA significantly decreased H(2)O(2)-induced downstream signaling and apoptosis in VSMCs. Together, these data indicate that LAR regulates Fyn/JAK2/STAT3 and Fyn/p38 MAPK pathways involved in ROS-induced apoptosis.
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PMID:Leukocyte antigen-related protein tyrosine phosphatase negatively regulates hydrogen peroxide-induced vascular smooth muscle cell apoptosis. 1885 10

Despite the growing body of evidence supporting prolactin (PRL) actions in human breast cancer, little is known regarding PRL regulation of its own receptor in these cells. Ligand-initiated endocytosis is a key process in the regulation of receptor availability and signaling cascades that may lead to oncogenic actions. Although exposure to exogenous PRL accelerates degradation of the long isoform of the PRL receptor (lPRLR), neither the signals initiated by PRL that lead to lPRLR internalization and subsequent down-regulation, nor the relationship to downstream pathways are understood in breast cancer cells. In this study, we showed that PRL-induced down-regulation of the lPRLR was reduced by inhibition of src family kinases (SFKs), but not Janus kinase 2, in MCF-7 cells. Inhibition of SFKs also resulted in accumulation of a PRL-induced PRLR fragment containing the extracellular domain, which appeared to be generated from newly synthesized PRLR. lPRLR was constitutively associated with SFKs in lipid rafts. PRL-induced SFK activation led to recruitment of the guanosine triphosphatase, dynamin-2, to an internalization complex, resulting in endocytosis. Inhibition of endocytosis by small interfering RNA-mediated knockdown of dynamin-2 blocked PRL-induced down-regulation of lPRLR, confirming that internalization is essential for this process. Endocytosis also was required for optimal phosphorylation of ERK1/2 and Akt, but not for Janus kinase 2 or signal transducer and activator of transcription 5, indicating that internalization selectively modulates signaling cascades. Together, these data indicate that SFKs are key mediators of ligand-initiated lPRLR internalization, down-regulation, and signal transduction in breast cancer cells, and underscore the importance of target cell context in receptor trafficking and signal transduction.
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PMID:SRC family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast cancer cells. 1905 63

We have previously shown that activation of nicotinic acetylcholine receptors (nAChRs) enhanced long-term potentiation (LTP) in the rat dentate gyrus in vitro via activation of alpha7 nAChR. In the present studies, mechanisms underlying the acute and chronic nicotinic enhancement of LTP were examined. In particular, the involvement of activation of intracellular kinases was examined using selective kinase antagonists, and the effects of enhancing cholinergic function with positive allosteric modulators of the alpha7 nAChR and with acetylcholinesterase (AChE) inhibitors were also investigated. Activation of extracellular signal-regulated kinase (ERK) and cAMP-dependent protein kinase (PKA) was found to be involved in the induction of the acute nicotinic enhancement of LTP, although not control LTP. In contrast, activation of the tyrosine kinase Src, Ca(2+)-calmodulin-dependent protein kinase II, Janus kinase 2 and p38 mitogen-activated protein kinase was not involved in the acute nicotinic enhancement of LTP, although Src activation was necessary for control LTP. Moreover, activation of phosphoinositide 3-kinase was involved in the acute nicotinic enhancement of LTP to a much lesser extent than in control LTP. Chronic nicotine enhancement of LTP was found to be dependent on PKA, ERK and Src kinases. Acute nicotinic enhancement of LTP was occluded by chronic nicotine treatment. The positive allosteric modulator PNU-120596 was found to strongly reduce the threshold for nicotinic enhancement of LTP, an affect mediated via the alpha7 nAChR as it was blocked by the selective antagonist methyllycaconitine. The AChE inhibitors tacrine and physostigmine enhanced control LTP.
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PMID:Intracellular mechanisms underlying the nicotinic enhancement of LTP in the rat dentate gyrus. 1907 24

Chemerin has recently been characterized as a novel adipokine playing a crucial role in adipocyte differentiation and insulin signalling. In the current study, the impact of insulin resistance-inducing and proinflammatory interleukin (IL)-1beta on chemerin protein secretion and mRNA expression was determined in 3T3-L1 adipocytes. Interestingly, IL-1beta significantly induced chemerin protein secretion almost 1.3-fold from 5.89 ng/ml (basal) to 7.52 ng/ml. Furthermore, chemerin mRNA synthesis was significantly stimulated by IL-1beta in a dose-dependent fashion with 1.5-fold induction seen at IL-1beta concentrations as low as 0.07 ng/ml and maximal 2.6-fold upregulation found at 2 ng/ml effector. Induction of chemerin mRNA by IL-1beta was time-dependent in both 3T3-L1 adipocytes and brown fat cells. Signalling studies suggested that Janus kinase 2, nuclear factor kappa B, p44/42 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase are involved in IL-1beta-induced chemerin mRNA expression. Furthermore, recombinant chemerin downregulated insulin-stimulated glucose uptake. Taken together, we show that chemerin is upregulated in fat cells by IL-1beta and might modulate the effects of IL-1beta on adipocyte metabolism and insulin sensitivity.
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PMID:Interleukin-1beta induces the novel adipokine chemerin in adipocytes in vitro. 1923 30

Mesenchymal stem cells (MSCs) migrate to tumors both in vitro and in vivo. Gene expression profiling analysis reveals that stromal cell-derived factor 1 (SDF-1) is significantly upregulated in MSCs exposed to tumor cell-conditioned medium, when compared with cells treated with control medium, suggesting that SDF-1 signaling is important in mediating MSC migration. This study investigates downstream signaling during MSC migration in response to tumor cell-conditioned medium and recombinant SDF-1 protein treatments. We observed that both recombinant SDF-1 and tumor cell-conditioned medium were able to activate downstream signaling via signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) as revealed by increased phosphorylation of STAT3 and ERK1/2 in human MSCs (hMSCs). Significant impairment of in vitro migration was observed in the presence of MAPK/ERK kinase (MEK) inhibitor PD98059, whereas two Janus kinase 2 (Jak2) inhibitors completely abolished migration induced by tumor cell-conditioned medium. Impaired MSC migration correlated with decreased levels of phosphorylated STAT3 and ERK1/2, suggesting that SDF-1 stimulation activates Jak2/STAT3 as well as MEK/ERK1/2 signaling, which in turn promotes migration of MSCs toward tumor cells. Furthermore, stimulation of hMSCs with recombinant SDF-1 and tumor cell-conditioned medium also significantly activated the focal adhesion kinases (FAKs) and paxillin, which correlated with reorganization of F-actin filaments in hMSCs. Decreased phosphorylation of FAK and paxillin as well as disruption of cytoskeleton organization was observed following Jak2 and MEK inhibitor treatment. Taken together, our results provide insight into the molecular pathways responsible for MSC migration toward the tumor microenvironment and may provide the molecular basis for modifying MSCs for therapeutic purposes.
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PMID:Activation of signal transducers and activators of transcription 3 and focal adhesion kinase by stromal cell-derived factor 1 is required for migration of human mesenchymal stem cells in response to tumor cell-conditioned medium. 1935 Jun 87

MCT2 is the predominant neuronal monocarboxylate transporter allowing lactate use as an alternative energy substrate. It is suggested that MCT2 is upregulated to meet enhanced energy demands after modifications in synaptic transmission. Brain-derived neurotrophic factor (BDNF), a promoter of synaptic plasticity, significantly increased MCT2 protein expression in cultured cortical neurons (as shown by immunocytochemistry and western blot) through a translational regulation at the synaptic level. Brain-derived neurotrophic factor can cause translational activation through different signaling pathways. Western blot analyses showed that p44/p42 mitogen-activated protein kinase (MAPK), Akt, and S6 were strongly phosphorylated on BDNF treatment. To determine by which signal transduction pathway(s) BDNF mediates its upregulation of MCT2 protein expression, the effect of specific inhibitors for p38 MAPK, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK), p44/p42 MAPK (ERK), and Janus kinase 2 (JAK2) was evaluated. It could be observed that the BDNF-induced increase in MCT2 protein expression was almost completely blocked by all inhibitors, except for JAK2. These data indicate that BDNF induces an increase in neuronal MCT2 protein expression by a mechanism involving a concomitant stimulation of PI3K/Akt/mTOR/S6, p38 MAPK, and p44/p42 MAPK. Moreover, our observations suggest that changes in MCT2 expression could participate in the process of synaptic plasticity induced by BDNF.
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PMID:Brain-derived neurotrophic factor enhances the expression of the monocarboxylate transporter 2 through translational activation in mouse cultured cortical neurons. 1979 95


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