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)

Recent studies have demonstrated that mitogen-activated protein kinases (MAPKs), including Jun N-terminus kinase (JNK), p38 and Erk, play crucial roles in cell migration. JNK, for example, regulates cell migration by phosphorylating paxillin, DCX, Jun and microtubule-associated proteins. Studies of p38 show that this MAPK modulates migration by phosphorylating MAPK-activated protein kinase 2/3 (MAPKAP 2/3), which appears to be important for directionality of migration. Erk governs cell movement by phosphorylating myosin light chain kinase (MLCK), calpain or FAK. Thus, the different kinases in the MAPK family all seem able to regulate cell migration but by distinct mechanisms.
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PMID:MAP kinases and cell migration. 1537 22

Protein kinases, particularly mitogen-activated protein kinases and receptor-tyrosine kinases play crucial roles in mammalian cellular metabolism by regulating intracellular signaling pathways that control proliferation, differentiation, cytokine gene induction and cytokine responsiveness, matrix metalloproteinase gene expression, mechanical transduction, as well as programmed cell death (apoptosis). Many of these pathways are also important components of cartilage homeostasis because alterations in intracellular signaling pathways appear to play a prominent role in chondrocyte dysfunction that is part of osteoarthritis pathogenesis and disease progression. Several mitogen-activated protein kinases and receptor-tyrosine kinases have been characterized as participating in chondrocyte signaling pathways. They are c-Jun-amino-terminal protein kinase, p38 kinase, extracellular signal-regulated protein kinase, and Ror2. Janus kinases and signal transducers and activators of transcription factors (Janus kinase/signal transducers and activators of transcription pathway) are also implicated in modulating the chondrogenic phenotype. Mitogen-activated protein kinase activation is required for their role as phosphorylating enzymes. Activation results from mitogen-activated protein kinase phosphorylation carried out by at least seven upstream kinases known as mitogen-activated protein kinase kinases. Additional upstream kinases (for example, MKKKKs and MKKKs) often require low molecular weight GTP-binding proteins to mediate the mitogen-activated protein-kinase kinases cascade. Identifying the functions of mitogen-activated protein kinases in normal and aging cartilage and the extent to which mitogen-activated protein kinases may be altered in osteoarthritis cartilage and synovium will be critical for developing novel therapies for osteoarthritis management.
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PMID:Protein kinases in chondrocyte signaling and osteoarthritis. 1548 58

Follicle-stimulating hormone (FSH) is necessary and sufficient to induce maturation of ovarian follicles to a mature, preovulatory phenotype in the intact animal, resulting in the generation of mature eggs and production of estrogen. FSH accomplishes these actions by inducing a complex pattern of gene expression in target granulosa cells that is regulated by input from many different signaling cascades, including those for the extracellular regulated kinases (ERKs), p38 mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K). The upstream kinase that appears to be responsible for initiating all of the signaling that regulates gene expression in these epithelial cells is protein kinase A (PKA). PKA not only signals to directly phosphorylate transcription factors like cAMP response element binding protein and to promote chromatin remodeling by phosphorylating histone H3, this versatile kinase also enhances the activity of the p38 MAPK, ERK, and PI3K pathways. Additionally, accumulating evidence suggests that activation of a single signaling cascade downstream of PKA is not sufficient to activate target gene expression. Rather, cross-talk between and among signaling cascades is required. We will review the signaling cascades activated by FSH in granulosa cells and how these cascades contribute to the regulation of select target gene expression.
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PMID:FSH signaling pathways in immature granulosa cells that regulate target gene expression: branching out from protein kinase A. 1661 57

The stress-activated c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (p38) regulate apoptosis induced by several forms of cellular insults. Potential targets for these kinases include members of the Bcl-2 family proteins, which mediate apoptosis generated through the mitochondria-initiated, intrinsic cell death pathway. Indeed, the activities of several Bcl-2 family proteins, both pro- and anti-apoptotic, are controlled by JNK phosphorylation. For example, the pro-apoptotic activity of Bim(EL), a member of the Bcl-2 family, is stimulated by JNK phosphorylation at Ser-65. In contrast, there is no reported evidence that p38-induced apoptosis is due to direct phosphorylation of Bcl-2 family proteins. Here we report evidence that sodium arsenite-induced apoptosis in PC12 cells may be due to direct phosphorylation of Bim(EL) at Ser-65 by p38. This conclusion is supported by data showing that ectopic expression of a wild type, but not a non-phosphorylatable S65A mutant of Bim(EL), potentiates sodium arsenite-induced apoptosis and by experiments showing direct phosphorylation of Bim(EL) at Ser-65 by p38 in vitro. Furthermore, sodium arsenite induced Bim(EL) phosphorylation at Ser-65, which was blocked by p38 inhibition. This study provides the first example whereby p38 induces apoptosis by phosphorylating a member of the Bcl-2 family and illustrates that phosphorylation of Bim(EL) on Ser-65 may be a common regulatory point for cell death induced by both JNK and p38 pathways.
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PMID:p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. 1681 94

Airway inflammation is an outcome of complex interactions of multiple cell types in an inflammatory network. In recent years, it has become clear that a single target approach is unlikely to be effective for the treatment of inflammatory airway diseases such as asthma. This recognition suggests an alternative approach of targeting multiple cell types and/or mediators. Airway smooth muscle (ASM) cells are unique in serving the dual function of bronchoconstriction and inflammation in the airway system. ASM cells respond to a large array of external stimuli such as acetylcholine, bradykinin, inflammatory cytokines, and cyclic stretch with the expression of inflammatory mediators such as cytokines and cyclooxygenase products. Ca(2+) influx through voltage-gated and transient receptor potential channels are important mechanisms of Ca(2+)-dependent transcription in ASM cells. Calcineurin and Ca(2+), calmodulin-dependent kinase (CaMK) are Ca(2+)-sensitive enzymes that regulate the activation of the two transcription factors, nuclear factor of activated T-cells (NFAT) and cyclic AMP response element binding protein (CREB). Erk1/2 and p38 mitogen-activated protein kinases are signaling enzymes that couple receptor activation to gene transcription by phosphorylating CREB and stabilizing mRNA against de-adenylation. CREB is a unique transcription factor that is phosphorylated by both CaMK II and Erk1/2 MAPK. Nuclear factor kappaB (NFkappaB) appears to be a universal transcription factor that regulates the transcription of almost all inflammatory genes. Detailed understanding of the cellular components and interactions in the inflammatory network of the airway system may lead to rational targeting of multiple cells and mediators in the treatment of airway inflammation.
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PMID:Airway smooth muscle cell as therapeutic target of inflammation. 1726 68

Eukaryotes generally rely on signal transduction by mitogen-activated protein kinases (MAPKs) for activating their regulatory pathways. However, the presence of a complete MAPK cascade in Plasmodium falciparum is debatable because a search of the entire genome did not portray known MAPK kinase (MAPKK) sequences. Via homology PCR experiments, only two copies of plasmodial MAPK homologues (Pfmap1 and Pfmap2) have been identified but their upstream activators remain unknown. In an earlier experiment, Pfnek3 was found to be an unusual activator of Pfmap2 in in vitro experiments, despite its molecular identity as a malarial protein kinase from the NIMA (Never in Mitosis, Aspergillus) family. In this study, the role of Pfnek3 as a likely upstream MAPKK is defined through molecular and biochemical characterization. Since a previous report proposes a TSH motif as an activation site of Pfmap2, its site-directed mutants, T290A, S291A, and H292K were constructed to elucidate the involvement of Pfnek3 in phosphorylating and activating Pfmap2 in a battery of kinase assays. The results suggested that residue T290 is the site of phosphorylation by Pfnek3. This supposition was further supported by liquid chromatography mass spectrometry. Although P. falciparum does not appear to possess a conventional MAPK cascade, they may rely on other kinases such as Pfnek3 to carry out similar phosphorylation to activate its signaling pathways.
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PMID:Pfnek3 functions as an atypical MAPKK in Plasmodium falciparum. 1766 47

p38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies.
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PMID:The p38 MAPK stress pathway as a tumor suppressor or more? 1850 57

Developmental thyroid hormone (TH) deficiency leads to mental retardation and neurological deficits in humans. In this study, congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water during gestation and suckling period. This treatment induced hyperphosphorylation of neurofilaments, the neuronal intermediate filament (IF) proteins, of heavy, medium and low molecular weight (NF-H, NF-M and NF-L, respectively) without altering the phosphorylation level of astrocyte IF proteins, glial fibrillary acidic protein (GFAP) and vimentin in cerebral cortex of rats. NF-H was hyperphosphorylated on KSP repeats in the carboxy-terminal tail domain. Furthermore, the immunocontent of GFAP and NF subunits was down-regulated, while vimentin was unaltered both in tissue homogenate and in cytoskeletal fraction of hypothyroid animals. Moreover, we verified the immunocontent of astrocyte glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) as well as activation of mitogen-activated protein kinases (MAPKs) in hypothyroid rats. Results showed that hypothyroidism is associated with decreased GLAST and GLT-1 immunocontent. Additionally, we demonstrated increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation without altering Jun N-terminal kinase (JNK) and p38(MAPK) phosphorylation. However, total JNK levels were down-regulated. Taken together, these results suggest that the thyroid status could modulate the integrity of neuronal cytoskeleton acting on the endogenous NF-associated phosphorylating system and that such effect could be related to glutamate-induced excitotoxicity, as well as ERK1/2 and JNK modulation. These events could be somehow related to the neurological dysfunction described in hypothyroidism.
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PMID:Congenital hypothyroidism is associated with intermediate filament misregulation, glutamate transporters down-regulation and MAPK activation in developing rat brain. 1884 85

The mitogen-activated protein kinases MEK/ERK pathway regulates fundamental processes in malignant cells and represents an attractive target in the development of new cancer treatments especially for human hepatocarcinoma highly resistant to chemotherapy. Although gene extinction experiments have suggested distinct roles for these proteins, the MEK/ERK cascade remains widely considered as exhibiting an overlap of functions. To investigate the functionality of each kinase in tumorigenesis, we have generated stably knock-down clones for MEK1/2 and ERK1/2 isoforms in the human hepatocellular carcinoma line HuH7. Our results have shown that RNAi strategy allows a specific disruption of the targeted kinases and argued for the critical function of MEK1 in liver tumor growth. Transient and stable extinction experiments demonstrated that MEK1 isoform acts as a major element in the signal transduction by phosphorylating ERK1 and ERK2 after growth factors stimulation, whereas oncogenic level of ERK1/2 phosphorylation appears to be MEK1 and MEK2 dependent in basal condition. In addition, silencing of MEK1 or ERK2 abolished cell proliferation and DNA replication in vitro as well as tumor growth in vivo after injection in rodent. In contrast, targeting MEK2 or ERK1 had no effect on hepatocarcinoma progression. These results strongly corroborate the relevance of targeting the MEK cascade as attested by pharmacologic drugs and support the potential application of RNAi in future development of more effective cancer therapies. Our study emphasizes the importance of the MEK/ERK pathway in human hepatocarcinoma cell growth and argues for a crucial role of MEK1 and ERK2 in this regulation.
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PMID:RNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivo. 1981 36

The mitogen-activated protein (MAP) kinases are ubiquitous intracellular signaling proteins that respond to a variety of extracellular signals and regulate most cellular functions including proliferation, apoptosis, migration, differentiation, and secretion. The four major MAP kinase family members, which include the ERK1/2, JNK, p38, and ERK5 proteins, coordinate cellular responses by phosphorylating and regulating the activity of dozens of substrate proteins involved in transcription, translation, and changes in cellular architecture. Uncontrolled activation of the MAP kinases has been implicated in the initiation and progression of a variety of cancers and inflammatory disorders. As such, the ability to manipulate the activity of MAP kinase proteins with specific pharmacological inhibitors has received much attention as research tools for understanding basic mechanisms of cellular functions and for clinical tools to treat diseases. A variety of pharmacological inhibitors have been developed to selectively block MAP kinases directly or indirectly through targeting upstream regulators. This chapter will provide an overview of some of the current inhibitors that target MAP kinase signaling pathways and provide methodology on how to use selective MAP kinase inhibitors and immunoblotting techniques to monitor and quantify phosphorylation of MAP kinase substrates.
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PMID:Use of inhibitors in the study of MAP kinases. 2081 79


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