Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac hypertrophy is induced by a variety of diseases, such as hypertension, valvular diseases, myocardial infarction, and endocrine disorders. Although cardiac hypertrophy may initially be a beneficial response that normalizes wall stress and maintains normal cardiac function, prolonged hypertrophy is a leading cause of heart failure and sudden death. A number of studies have elucidated molecules responsible for the development of cardiac hypertrophy, including the mitogen-activated protein (MAP) kinases pathway, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and calcium/calmodulin-dependent protein phosphatase calcineurin pathway. These molecules may be targets for therapies designed to prevent the progression of cardiac hypertrophy. Numerous studies have focused on characterization of the intracellular signal transduction molecules that promote cardiac hypertrophy in order to clarify the molecular mechanisms, but there have been only a few reports on the inhibitory regulators of hypertrophic response. Recently, several molecules have attracted much attention as endogenous inhibitory regulators of cardiac hypertrophy. Enhancement of these inhibitory regulators would also seem to be a potential approach for the pharmacological treatment of hypertrophy. In this review, we summarize the inhibitory molecules of cardiac hypertrophy.
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PMID:Inhibitory molecules in signal transduction pathways of cardiac hypertrophy. 1235 32

Smooth muscle caldesmon (CaD) binds F-actin and inhibits actomyosin ATPase activity. The inhibition is reversed by Ca2+/calmodulin (CaM). CaD is also phosphorylated upon stimulation at sites specific for mitogen-activated protein kinases (MAPKs). Because of these properties, CaD is thought to be involved in the regulation of smooth muscle contraction. The molecular mechanism of the reversal of inhibition is not well understood. We have expressed His6-tagged fragments containing the sequence of the C-terminal region of human (from M563 to V793) and chicken (from M563 to P771) CaD as well as a variant of the chicken isoform with a Q766C point mutation. By cleavages with proteases, followed by high-speed cosedimentation with F-actin and mass spectrometry, we found that within the C-terminal region of CaD there are multiple actin contact points forming two clusters. Intramolecular fluorescence resonance energy transfer between probes attached to cysteine residues (the endogenous C595 and the engineered C766) located in these two clusters revealed that the C-terminal region of CaD is elongated, but it becomes more compact when bound to actin. Binding of CaM restores the elongated conformation and facilitates dissociation of the C-terminal CaD fragment from F-actin. When the CaD fragment was phosphorylated with a MAPK, only one of the two actin-binding clusters dissociated from F-actin, whereas the other remained bound. Taken together, these results demonstrate that while both Ca2+/CaM and MAPK phosphorylation govern CaD's function via a conformational change, the regulatory mechanisms are different.
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PMID:Caldesmon binding to actin is regulated by calmodulin and phosphorylation via different mechanisms. 1261 45

Although the development of behavioral sensitization to psychostimulants such as cocaine and amphetamine is confined mainly to one nucleus in the brain, the ventral tegmental area (VTA), this process is nonetheless complex, involving a complicated interplay between neurotransmitters, neuropeptides and trophic factors. In the present review we present the hypothesis that calcium-stimulated second messengers, including the calcium/calmodulin-dependent protein kinases and the Ras/mitogen-activated protein kinases, represent the major biochemical pathways whereby converging extracellular signals are integrated and amplified, resulting in the biochemical and molecular changes in dopaminergic neurons in the VTA that represent the critical neuronal correlates of the development of behavioral sensitization to psychostimulants. Moreover, given the important role of calcium-stimulated second messengers in the expression of behavioral sensitization, these signal transduction systems may represent the biochemical substrate through which the transient neurochemical changes associated with the development of behavioral sensitization are translated into the persistent neurochemical, biochemical and molecular alterations in neuronal function that underlie the long-term expression of psychostimulant-induced behavioral sensitization.
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PMID:The roles of calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the development of psychostimulant-induced behavioral sensitization. 1264 23

Recently, we reported the cloning and preliminary characterization of a novel human immunomodulator named PLIF (placenta immunomodulatory ferritin). PLIF has a unique molecular structure, which is composed of a ferritin heavy chain-like domain and a novel cytokine-like domain called C48. Both intact molecule and C48 inhibit T cell proliferation following allogeneic or anti-CD3 stimuli. PLIF is localized at the fetal-maternal interface of human placenta and might play a role in down-modulating the maternal immune reaction toward the embryo. The inhibitory effect of PLIF on T cell activation can be direct, indirect through cytokine mediators, or both. In the present study we investigated the possible indirect effects of PLIF by using its bioactive domain C48. Measurement of various cytokines revealed that C48, predominantly, induce pronounced and rapid IL-10 production in monocytes, which is immune activation-independent. Further, we discovered that C48-induced IL-10 production is mediated through a calcium/calmodulin-p38 mitogen-activated protein (MAP) kinase signaling pathway. However, extracellular signal-related kinases1,2 (ERK1,2), also activated by C48 stimulation, exhibited a limiting effect on IL-10 production.
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PMID:PLIF induces IL-10 production in monocytes: a calmodulin-p38 mitogen-activated protein kinase-dependent pathway. 1267 Aug 72

During action potential firing, the rate of synapsin dissociation from synaptic vesicles and dispersion into axons controls the rate of vesicle availability for exocytosis at the plasma membrane. Here we show that synapsin Ia's dispersion rate tracks the synaptic vesicle pool turnover rate linearly over the range 5-20 Hz and that the molecular basis for this lies in regulation at both the calcium-calmodulin-dependent kinase (CaM kinase) and the mitogen-activated protein (MAP) kinase/calcineurin sites. Our results show that CaM kinase sites control vesicle mobilization at low stimulus frequency, while MAP kinase/calcineurin sites are critical at both lower and higher stimulus frequencies. Thus, multiple signaling pathways serve to allow synapsin's control of vesicle mobilization over different stimulus frequencies.
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PMID:Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. 1269 65

Nerve growth factor (NGF) causes a rapid sensitisation of nociceptive sensory neurones to painful thermal stimuli owing to an action on the heat and capsaicin receptor TRPV1 (formerly known as VR1). We have developed a new technique to study this rapid sensitisation of TRPV1 by monitoring the effects of NGF on the increase in intracellular calcium concentration ([Ca2+]i) following exposure to capsaicin. Brief applications of capsaicin caused a rise in [Ca2+]i, and NGF was found to enhance this rise in 37 % of capsaicin-responsive neurones within 2 min. Pathways responsible for transducing the sensitisation of TRPV1 by TrkA, the NGF receptor, were characterised by observing the effects of inhibitors of key members of NGF-activated second messenger signalling cascades. Specific inhibitors of the ras/MEK (mitogen-activated protein and extracellular signal-regulated kinases) pathway and of phospholipase C did not abolish the NGF-induced sensitisation, but wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), totally abolished the effect of NGF. Pharmacological blockade of protein kinase C (PKC) or calcium-calmodulin-dependent protein kinase II (CaMK II) activation also prevented NGF-induced sensitisation, while blockade of protein kinase A (PKA) was without effect. These data indicate that the crucial early pathway activated by NGF involves PI3K, while PKC and CaMK II are also involved, probably at subsequent stages of the NGF-activated signalling pathway.
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PMID:Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. 1281 88

Our goal in this review is to provide a comprehensive, integrated view of the numerous signaling pathways that are activated by alpha(1)-adrenoceptors and control actin-myosin interactions (i.e., crossbridge cycling and force generation) in mammalian arterial smooth muscle. These signaling pathways may be categorized broadly as leading either to thick (myosin) filament regulation or to thin (actin) filament regulation. Thick filament regulation encompasses both "Ca(2+) activation" and "Ca(2+)-sensitization" as it involves both activation of myosin light chain kinase (MLCK) by Ca(2+)-calmodulin and regulation of myosin light chain phosphatase (MLCP) activity. With respect to Ca(2+) activation, adrenergically induced Ca(2+) transients in individual smooth muscle cells of intact arteries are now being shown by high resolution imaging to be sarcoplasmic reticulum-dependent asynchronous propagating Ca(2+) waves. These waves differ from the spatially uniform increases in [Ca(2+)] previously assumed. Similarly, imaging during adrenergic activation has revealed the dynamic translocation, to membranes and other subcellular sites, of protein kinases (e.g., Ca(2+)-activated protein kinases, PKCs) that are involved in regulation of MLCP and thus in "Ca(2+) sensitization" of contraction. Thin filament regulation includes the possible disinhibition of actin-myosin interactions by phosphorylation of CaD, possibly by mitogen-activated protein (MAP) kinases that are also translocated during adrenergic activation. An hypothesis for the mechanisms of adrenergic activation of small arteries is advanced. This involves asynchronous Ca(2+) waves in individual SMC, synchronous Ca(2+) oscillations (at high levels of adrenergic activation), Ca(2+) sparks, "Ca(2+)-sensitization" by PKC and Rho-associated kinase (ROK), and thin filament mechanisms.
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PMID:Alpha1-adrenergic signaling mechanisms in contraction of resistance arteries. 1288 52

This review examines signal transduction pathways mediating agonist-induced contraction of circular muscle in the body of the esophagus and in the lower esophageal sphincter (LES). In the LES, circular muscle agonists activate a well-defined contractile pathway, involving calcium (Ca(2+))-induced activation of calmodulin and myosin kinase, causing phosphorylation of 20-kDa myosin light chains (MLCs) and contraction. In this pathway, phosphorylation and contraction may be modulated by other factors, resulting, for instance, in inhibition of phosphatase activity, which may potentiate MLC phosphorylation. The agonist-activated contractile pathway of circular muscle from the esophageal body is not as well defined, and it is different from the LES contractile pathway, as it depends on activation of a Ca(2+)-independent protein kinase C (PKC), PKC-epsilon. In this pathway, agonist-induced Ca(2+) influx and/or release activate phospholipases to produce second messengers, such as diacylglycerol and arachidonic acid. The second messengers, however, activate a PKC-epsilon and a contractile pathway, which is Ca(2+) independent. This contractile pathway depends on activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 and of p38 MAP kinase. These kinases are, in turn, linked to the small heat-shock protein HSP27, to integrin-linked kinase, and perhaps to other Ca(2+)-independent kinases, such as zipper kinase capable of producing MLC phosphorylation and contraction.
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PMID:Calcium-dependent and calcium-independent contractions in smooth muscles. 1292 71

Neurogranin/RC3 (Ng) is a postsynaptic protein kinase C (PKC) substrate and calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by Ca2+, phosphorylation and oxidation. Ng has been implicated in the modulation of postsynaptic signal transduction pathways and synaptic plasticity. Previously, we showed a severe deficit of spatial memory in Ng knockout (KO) mice. Activation of the NMDA receptor and its downstream signaling molecules are known to be involved in long-term memory formation. In the present study, using mouse hippocampal slices, we demonstrated that NMDA induced a rapid and transient phosphorylation and oxidation of Ng. NMDA also caused activation of PKC as evidenced by their phosphorylations, whereas, such activations were greatly reduced in the KO mice. A higher degree of phosphorylation of Ca2+/CaM-dependent kinase II and activation of cyclic AMP-dependent protein kinase were also evident in the WT compared to those of the KO mice. Phosphorylation of downstream targets, including mitogen-activated protein kinases and cAMP response element-binding protein, were significantly attenuated in the KO mice. These results suggest that by its Ca2+-sensitive CaM-binding feature, and through its phosphorylation and oxidation, Ng regulates the Ca2+- and Ca2+/CaM-dependent signaling pathways subsequent to the stimulation of NMDA receptor. These findings support the hypothesis that the derangement of hippocampal signal transduction cascades in Ng KO mice causes the deficits in synaptic plasticity, learning and memory that occur in these mice.
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PMID:Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+- and Ca2+/calmodulin-dependent neuronal signaling in the hippocampus. 1295 Apr 61

Deactivation of brain macrophages (microglia) by transforming growth factor-beta (TGF-beta) is characterized by enhanced Kv1.3 K+ channel expression. The intracellular mechanisms by which TGF-beta causes K+ channel upregulation in microglia have remained unclear. We show here that the protein kinase inhibitor H7 abolishes TGF-beta-induced increases in delayed rectifier K+ current density. However, this effect cannot be related to inhibition of protein kinase C (PKC) or protein kinase A (PKA) activity, because specific PKC and PKA inhibitors did not exhibit effects identical to H7. TGF-beta-induced Kv1.3 channel expression was also unaffected by inhibitors of tyrosine kinase, Ca2+/calmodulin kinase II and mitogen-activated protein (MAP) kinase ERK. In contrast, delayed rectifier K+ current density was larger in TGF-beta-stimulated cells pretreated with the p38 MAP kinase inhibitor SB203580 or the phosphatidylinositol 3-OH (PI3) kinase inhibitor wortmannin, suggesting that both p38 MAP kinase and PI3 kinase regulate negatively the upregulation of Kv1.3 K+ channels in TGF-beta-treated microglial cells.
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PMID:Effects of kinase inhibitors on TGF-beta induced upregulation of Kv1.3 K+ channels in brain macrophages. 1296 Oct 89


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