Gene/Protein Disease Symptom Drug Enzyme Compound
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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 ability of neurotrophins to modulate the survival and differentiation of neuronal populations involves the Trk/MAP (mitogen-activated protein kinase) kinase signaling pathway. More recently, neurotrophins have also been shown to regulate synaptic transmission. The synapsins are a family of neuron-specific phosphoproteins that play a role in regulation of neurotransmitter release, in axonal elongation, and in formation and maintenance of synaptic contacts. We report here that synapsin I is a downstream effector for the neurotrophin/Trk/MAP kinase cascade. Using purified components, we show that MAP kinase stoichiometrically phosphorylated synapsin I at three sites (Ser-62, Ser-67, and Ser-549). Phosphorylation of these sites was detected in rat brain homogenates, in cultured cerebrocortical neurons, and in isolated presynaptic terminals. Brain-derived neurotrophic factor and nerve growth factor upregulated phosphorylation of synapsin I at MAP kinase-dependent sites in intact cerebrocortical neurons and PC12 cells, respectively, while KCl- induced depolarization of cultured neurons decreased the phosphorylation state at these sites. MAP kinase-dependent phosphorylation of synapsin I significantly reduced its ability to promote G-actin polymerization and to bundle actin filaments. The results suggest that MAP kinase-dependent phosphorylation of synapsin I may contribute to the modulation of synaptic plasticity by neurotrophins and by other signaling pathways that converge at the level of MAP kinase activation.
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PMID:Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. 862 96

Murine P19 embryonal carcinoma (EC) cells can be differentiated into various germ layer derivatives. The addition of retinoic acid (RA) to P19-EC cell aggregates results in a transient activation of receptor protein tyrosine phosphatase-alpha (RPTP alpha). Subsequent replating of these aggregates leads to neuronal differentiation. P19-EC cells expressing constitutively active RPTP alpha (P19-RPTP alpha) show extensive neuronal differentiation upon RA treatment in monolayer. P19-RPTP alpha cells thus provide a suitable in vitro model for studying neuronal differentiation. We used P19-RPTP alpha cells to study the effects of activin and basic fibroblast growth factor (bFGF) on neurogenesis. We show that P19-RPTP alpha cells express mRNA for types I and II activin receptors. RA addition causes an up-regulation of receptor type IIA expression. Complexes of type I and II receptors were detectable by cross-linking assays both before and after RA treatment. Receptor complexes were functional as determined by transient transfection assays with activin responsive reporter constructs. Undifferentiated as well as differentiated P19-RPTP alpha cells express also the FGF receptors (FGFRs) FGFR-1 and FGFR-2 but not FGFR-3 and FGFR-4. Their functionality was established by bFGF induced mitogen-activated protein kinase phosphorylation. Activin and bFGF appeared to exert differential actions on RA-induced neuronal differentiation. Although activin irreversibly changes the differentiation fate into nonneuronal directions, bFGF does not affect initial neurogenesis but regulates axonal outgrowth in a concentration-dependent way; low concentrations of bFGF enhance axonal outgrowth, whereas high concentrations inhibit this process. These results strengthen the notion that activin and bFGF are important regulators of neurogenesis in the mammalian embryo.
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PMID:Activin and basic fibroblast growth factor regulate neurogenesis of murine embryonal carcinoma cells. 895 36

Eph family receptor tyrosine kinases signal axonal guidance, neuronal bundling, and angiogenesis; yet the signaling systems that couple these receptors to targeting and cell-cell assembly responses are incompletely defined. Functional links to regulators of cytoskeletal structure are anticipated based on receptor mediated cell-cell aggregation and migratory responses. We used two-hybrid interaction cloning to identify EphB1-interactive proteins. Six independent cDNAs encoding the SH2 domain of the adapter protein, Nck, were recovered in a screen of a murine embryonic library. We mapped the EphB1 subdomain that binds Nck and its Drosophila homologue, DOCK, to the juxtamembrane region. Within this subdomain, Tyr594 was required for Nck binding. In P19 embryonal carcinoma cells, activation of EphB1 (ELK) by its ligand, ephrin-B1/Fc, recruited Nck to native receptor complexes and activated c-Jun kinase (JNK/SAPK). Transient overexpression of mutant EphB1 receptors (Y594F) blocked Nck recruitment to EphB1, attenuated downstream JNK activation, and blocked cell attachment responses. These findings identify Nck as an important intermediary linking EphB1 signaling to JNK.
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PMID:Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. 943 Jun 61

Genetic analysis has enhanced our understanding of the biological roles of many protein tyrosine kinases (PTKs). More recently, studies utilizing both spontaneous mutants and mutants induced by homologous recombination techniques have begun to yield key insights into the role of specific protein tyrosine phosphatases (PTPs) and to suggest how PTKs and PTPs interact. Specific PTPs in Saccharomyces cerevesiae and Schizomyces pombe regulate MAP kinase pathways. Several Drosophila receptor PTPs control axonal targeting pathways, whereas the non-receptor PTP Corkscrew (Csw), plays an essential positive signaling role in multiple developmental pathways directed by receptor PTKs. The vertebrate homolog of Csw, SHP-2, also is required for growth factor signaling and normal development. Finally, very recent studies of other mammalian PTPs suggest that they have critical roles in processes as diverse as hematopoiesis and liver and pituitary development.
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PMID:Genetic analysis of protein tyrosine phosphatases. 952 14

We have used adult mouse superior cervical ganglia (SCG) to study the role of mitogen activated protein (MAP) kinase activity during axonal outgrowth in vitro. An initial peak in activity within the first hours of culture was followed by a substantially higher activity after 1 to 2 days, a time when axons were actively growing. The latter peak is probably a result of both higher levels of protein and increased activity. The addition of nerve growth factor stimulated both outgrowth and kinase activity, whereas treating the cultures with the kinase inhibitor PD98059 had an opposite effect. Taken together, the results suggest that activation of the MAP kinase pathway could be involved in the initiation as well as regulation of axonal outgrowth from adult SCG.
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PMID:Mitogen activated protein (MAP) kinase activity is increased in adult mouse superior cervical ganglia during culturing. 958 90

This article reviews current knowledge of neurofilament structure, phosphorylation, and function and neurofilament involvement in disease. Neurofilaments are obligate heteropolymers requiring the NF-L subunit together with either the NF-M or the NF-H subunit for polymer formation. Neurofilaments are very dynamic structures; they contain phosphorylation sites for a large number of protein kinases, including protein kinase A (PKA), protein kinase C (PKC), cyclin-dependent kinase 5 (Cdk5), extracellular signal regulated kinase (ERK), glycogen synthase kinase-3 (GSK-3), and stress-activated protein kinase gamma (SAPK gamma). Most of the neurofilament phosphorylation sites, located in tail regions of NF-M and NF-H, consist of the repeat sequence motif, Lys-Ser-Pro (KSP). In addition to the well-established role of neurofilaments in the control of axon caliber, there is growing evidence based on transgenic mouse studies that neurofilaments can affect the dynamics and perhaps the function of other cytoskeletal elements, such as microtubules and actin filaments. Perturbations in phosphorylation or in metabolism of neurofilaments are frequently observed in neurodegenerative diseases. A down-regulation of mRNA encoding neurofilament proteins and the presence of neurofilament deposits are common features of human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. Although the extent to which neurofilament abnormalities contribute to pathogenesis in these human diseases remains unknown, emerging evidence, based primarily on transgenic mouse studies and on the discovery of deletion mutations in the NF-H gene of some ALS eases, suggests that disorganized neurofilaments can provoke selective degeneration and death of neurons. An interference of axonal transport by disorganized neurofilaments has been proposed as one possible mechanism of neurofilament-induced pathology. Other factors that can potentially lead to the accumulation of neurofilaments will be discussed as well as the emerging evidence for neurofilaments as being possible targets of oxidative damage by mutations in the superoxide dismutase enzyme (SOD1); such mutations are responsible for approximately 20% of familial ALS cases.
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PMID:Neurofilaments in health and disease. 975 17

The neural cell adhesion molecule NCAM plays an important role in axonal growth, learning, and memory. A signaling pathway has been elucidated in which clustering of the NCAM140 isoform in the neural plasma membrane stimulated the activating phosphorylation of mitogen-activated protein kinases (MAPKs) and the transcription factor cyclic AMP response-element binding protein (CREB). NCAM clustering transiently induced dual phosphorylation (activation) of the MAPKs ERK1 and ERK2 (extracellular signal-regulated kinases) by a pathway regulated by the focal adhesion kinase p125fak, p59fyn, Ras, and MAPK kinase. CREB phosphorylation at serine 133 induced by NCAM was dependent in part on an intact MAPK pathway. c-Jun N-terminal kinase, which is associated with apoptosis and cellular stress, was not activated by NCAM. Inhibition of the MAPK pathway in rat cerebellar neuron cultures selectively reduced NCAM-stimulated neurite outgrowth. These results define an NCAM signal transduction mechanism with the potential for modulating the expression of genes needed for axonal growth, survival, and synaptic plasticity.
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PMID:NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. 1008 88

Neurofilaments (NFs) are neuron-specific intermediate filaments, and are the major cytoskeletal component in large myelinated axons. Lysine-serine-proline (KSP) repeats in the tail domains of high molecular weight NF proteins (NF-M and NF-H) are extensively phosphorylated in vivo in the axon. This phosphorylation in the tail domain has been postulated to play an important role in mediating neuron-specific properties, including axonal caliber and conduction velocity. Recent studies have shown that the mitogen-activated protein kinases (extracellular signal-regulated kinases, Erk1 and Erk2) phosphorylate KSP motifs in peptide substrates derived from the NF-M and NF-H tail domains in vitro. However, it is not clear whether activation of the mitogen activated protein (MAP) kinase pathway is able to phosphorylate these domains in vivo. To answer this question, a constitutively active form of mitogen-activated Erk activating kinase (MEK1) was cotransfected with an NF-M expression construct into NIH 3T3 cells. The activated mutant, but not the dominant negative mutant, induced phosphorylation of NF-M. In addition, it was shown that epidermal growth factor, which induces the MAP kinase cascade in NIH 3T3 cells, also activated endogenous Erk1 and Erk2 and NF-M tail domain phosphorylation in the transfected cells. These results present direct evidence that in-vivo activation of Erk1 and Erk 2 is sufficient for NF-M tail domain phosphorylation in transfected cells.
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PMID:Activation of mitogen-activated protein kinases (Erk1 and Erk2) cascade results in phosphorylation of NF-M tail domains in transfected NIH 3T3 cells. 1023 83

Several distinct classes of proteins positively regulate axonal growth; some of these are known to activate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascade, at least in nonneuronal cells. We have found that N-cadherin, as well as laminin (LN) and basic fibroblast growth factor (bFGF), can activate ERK in embryonic chick retinal neurons. Additionally, adhesion of retinal neurons to LN or N-cadherin substrates induced a redistribution of ERK from the cytoplasm toward the plasma membrane. Neurite outgrowth induced by bFGF, LN, or N-cadherin was strongly inhibited by treatment with inhibitors of ERK kinase activation, but not by an inhibitor of p38 MAPK. We conclude (1) that N-cadherin and LN can activate ERK in retinal neurons and (2) that activation of ERK is required for full neurite outgrowth induced by these proteins. Our results suggest that ERK activation is one point of convergence for signaling pathways generated by a variety of axon growth inducers.
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PMID:Distinct neurite outgrowth signaling pathways converge on ERK activation. 1035 98

Receptor-like protein tyrosine phosphatase kappa (RPTPkappa) is expressed in the nervous system in a manner consistent with a role in axonal growth and guidance. The extracellular domain of RPTPkappa shares structural features with cell adhesion molecules and can support homophilic adhesion. In the present study we produced a soluble Fc-chimeric protein containing the full extracellular domain of RPTPkappa. Following affinity capture, the RPTPkappa-Fc was shown to promote the aggregation of Covasphere beads, confirming its homophilic binding activity. When added to cultures of cerebellar neurons as a soluble molecule, the RPTPkappa chimera stimulated neurite outgrowth. The neurite outgrowth response was substantially inhibited by a cell-permeable peptide inhibitor of Grb2 and by PD 098059, a drug that has been used to inhibit MEK1 activation in a wide range of cell types. These results demonstrate that RPTPkappa can stimulate neurite outgrowth and provide evidence that this might involve the coupling of Grb2 to a MAPK signal transduction cascade.
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PMID:A soluble version of the receptor-like protein tyrosine phosphatase kappa stimulates neurite outgrowth via a Grb2/MEK1-dependent signaling cascade. 1038 29


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