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 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.
 ...
PMID:NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. 1008 88

Calcium has long been recognized as a key player in the control of axonal growth and guidance. Recent studies lend support to this pivotal role by showing that local changes in calcium can directly induce the formation of filopodia in vivo and turn a growth cone in vitro. Under normal growth conditions, the L1 adhesion molecule has now been shown to induce local rather than global changes in calcium in growth cones, and this suggests that cell adhesion molecules (CAMs) use localized calcium transients to stimulate axonal growth and guidance. A number of recent reports have demonstrated that the neurite outgrowth response stimulated by L1 and other adhesion molecules (NCAM, N-cadherin, laminin) also depends in part upon the integrity of the MAPK cascade in cells. In this review we consider the recent data and suggest that calcium and the MAPK cascade might be required for very distinct growth cone functions. Finally, we will consider the contentious issue of how the above CAMs activate signaling cascades in growth cones and review the recently available data that support the hypothesis that at least one of these CAMs (N-cadherin) might promote growth cone motility by directly interacting with the FGFR in growth cones.
 ...
PMID:CAMs and axonal growth: a critical evaluation of the role of calcium and the MAPK cascade. 1108 68

Bone morphogenetic protein-4 (BMP-4) induces epidermis and represses neural fate in Xenopus ectoderm. Our previous findings implicate p42 Erk MAP kinase (MAPK) in the response to neural induction. We have examined the effects of BMP-4 on MAPK activity in gastrula ectoderm. Expression of a dominant negative BMP-4 receptor resulted in a 4.5-fold elevation in MAPK activity in midgastrula ectoderm. MAPK activity was reduced in ectoderm expressing a constitutively active BMP-4 receptor, or ectoderm treated with BMP-4 protein in the presence or absence of cycloheximide. Overexpression of TAK1 led to a reduction in MAPK activity in early gastrula ectoderm. The inhibitory effects of TAK1 could be reversed by 1 microM SB 203580, a p38 inhibitor. Treatment of isolated ectoderm with SB 203580 led to expression of otx2, NCAM, and noggin. Western blot analyses indicated that the BMP-4 pathway does not activate JNKs in ectoderm. Our findings indicate that BMP-4 inhibits ectodermal MAPK activity through a TAK1/p38-type pathway. MAPK has been shown to inactivate Smad1. Thus, our results suggest that BMP-4 and MAPK pathways are mutually antagonistic in Xenopus ectoderm, and that interactions between these pathways may govern the choice between epidermal and neural fate.
 ...
PMID:Regulation of MAP kinase by the BMP-4/TAK1 pathway in Xenopus ectoderm. 1147 70

NCAM plays a key role in neural development and plasticity-mediating cell adhesion and differentiation mainly through homophilic binding. Until recently, attempts to modulate neuronal differentiation and plasticity through NCAM have been impeded by the absence of small synthetic agonists mimicking homophilic interactions of NCAM. We show here that a peptide, P2, corresponding to a 12-amino acid sequence localized in the FG loop of the second Ig module of NCAM, binds to the first Ig module, which is the natural binding partner of the second Ig module, with an apparent K(d) of 4.7 +/- 0.9 x 10(-6) m. P2 inhibits cell aggregation and induces neurite outgrowth from hippocampal neurons, maximal neuritogenic effect being obtained at a concentration of 0.8 microm. The neuritogenic effect was inhibited by preincubation of P2 with the recombinant NCAM-IgI. Both the length of P2 and the basic amino acid residues at the N and C termini are important for its neuritogenic activity. Treatment of hippocampal cultures with P2 results in induction of phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2. Thus, P2 is a potent mimetic of NCAM, and therefore, an attractive compound for the development of drugs for the treatment of neurodegenerative diseases.
 ...
PMID:Induction of neuronal differentiation by a peptide corresponding to the homophilic binding site of the second Ig module of the neural cell adhesion molecule. 1198 82

Functional PRL receptors are expressed in the human endometrium during the secretory phase of the menstrual cycle in which PRL stimulates tyrosine phosphorylation of Janus kinase 2 and STAT (signal transducer and activator of transcription) 1 and 5. In this study, we investigated the effect of PRL on the MAPK/ERK pathway in the human endometrium. Human endometrial tissue was collected during the mid to late secretory phase of the menstrual cycle. Western blot analysis performed on proteins, extracted after up to 30 min culture with PRL, demonstrated rapid tyrosine and threonine phosphorylation of ERK 1 and 2 MAPKs. The phosphorylation of ERK, in response to PRL, was localized by immunohistochemistry to glandular epithelial cells and a subset of stromal cells. Using immunofluorescence histochemistry, PRL-induced phosphorylation of ERK in the stromal compartment was localized to the uterine-specific CD56(+) natural killer (NK) cells. We have demonstrated that the PRL receptor is expressed in uterine CD56(+) NK cells in situ by immunofluorescence and in purified decidual CD56(+) NK cells by RT-PCR and Western blotting analysis. We have further demonstrated phosphorylation of ERK 1 and 2 in cultures of purified uterine CD56(+) NK cells, in response to PRL. Our data demonstrate that PRL stimulates the ERK pathway in multiple cellular compartments of the human endometrium and identify uterine CD56(+) NK cells as novel PRL target cells.
 ...
PMID:Prolactin induces ERK phosphorylation in epithelial and CD56(+) natural killer cells of the human endometrium. 1199 84

Neural cell adhesion molecules of the immunoglobulin superfamily are multidomain proteins involved in important cellular events pertinent to development and adult neurological function. This review attempts to give a concise overview of the complex intracellular signaling pathways enabling neural cell adhesion molecules NCAM and L1 to regulate axon growth, guidance, and synaptic plasticity. Recent research findings suggest that these molecules signal in part through integrins leading to cytoskeletal rearrangements locally in the growth cone or cell leading edge, and to MAP kinase, which has the potential to cause gene expression changes in the nucleus. Abnormal expression of NCAM on human chromosome 11q23 has been linked to schizophrenia in humans, a multigenic disease believed to be of neurodevelopmental origin. L1 at Xq28 is the target for mutation in a complex mental retardation disorder termed the L1 syndrome (also sometimes referred to as CRASH syndrome). Thus a full understanding of the mechanism of NCAM and L1 function will contribute to understanding both normal brain development and pathologies associated with cognitive dysfunction in schizophrenia and mental retardation.
 ...
PMID:Cellular signalling mechanisms of neural cell adhesion molecules. 1270 44

It was recently reported that glia cell line-derived neurotrophic factor (GDNF) facilitates presynaptic axonal growth and neurotransmitter release at neuromuscular synapses. Little is known, however, whether GDNF can also act on the postsynaptic apparatus and its underlying mechanisms. Using biochemical cold blocking of existing membrane acetylcholine receptors (AchRs) and biotinylation of newly inserted receptors we demonstrate that GDNF increases the insertion of AChRs into the surface membrane of mouse primary cultured muscle cells and that this does not require protein synthesis. Quantitative data from double-label imaging indicate that GDNF induces a quick and substantial increase in AchR insertion as well as lateral movement into AchR aggregates, relative to a weak effect on reducing the loss of receptors from pre-existing AchR aggregates, which in contrast to the effect of PMA. These effects occur in both innervated and un-innervated muscles, and GDNF affects nerve-muscle co-cultures more than it affects muscle-only cultures. Neurturin, another member of GDNF-family ligands has similar effects on AchRs as GDNF but the unrelated growth factor, EGF does not. Studies on protein phosphorylation and specific inhibitors of cell signal transduction indicate that GDNF function is mediated by receptor GFRalpha1 and involves MAPK, cAMP/cAMP responsive element-binding factor and Src kinase activities. GDNF may signal through c-Ret as well as NCAM-140 pathways since both the signaling receptors are expressed in the neuromuscular junction (NMJ). These data suggest that GDNF is an autocrine regulator of NMJ to promote the insertion and stabilization of postsynaptic AchRs. In vivo, GDNF may function as a synaptotrophic modulator for both pre- and postsynaptic differentiation to strengthen the functional and structural connections between nerve and muscle, and contribute to the synaptogenesis and plasticity of neuromuscular synapses.
 ...
PMID:Glia cell line-derived neurotrophic factor regulates the distribution of acetylcholine receptors in mouse primary skeletal muscle cells. 1538 Dec 79

Defective heme synthesis may cause acute porphyrias, which are associated with a wide array of neurological disturbances involving both the central and peripheral nervous systems. Thus, the understanding of the roles of heme in neuronal cell function may provide insights into the molecular events underlying the pathogenesis of neuropathies associated with defective heme synthesis. In this report, we use rat pheochromocytoma (PC12) clonal cells as a model system for studying the role of heme in neuronal cell survival. We examined the effects of inhibition of heme synthesis on signaling pathways and gene expression in nerve growth factor (NGF)-induced PC12 cells. We found that succinyl acetone-induced heme deficiency selectively caused apoptosis in NGF-induced PC12 cells. Further, we found that in succinyl acetone-treated, NGF-induced cells, the pro-survival Ras-ERK1/2 signaling pathway was inactivated and the pro-apoptotic JNK signaling pathway was activated. In these cells, the activation of caspase and the cleavage of nuclear poly (ADP-ribose) polymerase (PARP) were also evident. Importantly, microarray gene expression analysis showed that more than 20 key neuronal genes that were induced by NGF were suppressed by succinyl acetone. These genes include those encoding survival motor neuron protein, synaptic vesicle protein SVOP, and neural cell adhesion molecule NCAM. These results indicate that heme is important for neuronal cell signaling and the proper functioning of neuronal cells.
 ...
PMID:Heme deficiency suppresses the expression of key neuronal genes and causes neuronal cell death. 1595 Jul 57

The neural cell adhesion molecule NCAM and its glycosylation with polysialic acid (polySia) are crucially involved in proliferation, migration and differentiation of neural progenitors. Modification with polySia, homophilic and heterophilic interactions set the function of NCAM, but little is known on their interplay. We have shown recently that removal of polySia induces neuronal differentiation via heterophilic NCAM interactions at cell contacts between SH-SY5Y neuroblastoma cells. Here we analyze the additional impact of NCAM-positive fibroblasts as a ligand-presenting cellular environment, a model often used to demonstrate the neuritogenic effect of homophilic NCAM interactions. Native SH-SY5Y cells did not respond to interactions with fibroblast NCAM. However, after induction of neuronal differentiation by retinoic acid the previously ineffective NCAM signals activated extracellular signal-regulated kinase (ERK) and promoted neuritogenesis. Removal of polySia increased neuritogenesis in retinoic acid-treated cells additive to the NCAM substrate effect. The change in responsiveness to substrate NCAM was associated with a rearrangement of polysialylated NCAM away from its enrichment at homotypic cell-cell contacts and with the appearance of non-polysialylated NCAM, i.e. changes facilitating NCAM interactions with the substrate. Thus, heterophilic and homophilic NCAM interactions are integrated into the cell's response yet they have the capacity to independently trigger neuritogenesis. The actual occurrence of each of these interactions, however, depends on the cellular context, targeted cell surface presentation of NCAM and the dynamic regulation of its modification by polysialic acid. In summary, this study reveals how the complex interplay of NCAM interactions and polysialylation provides an elaborate system to regulate neuritogenesis.
 ...
PMID:The neural cell adhesion molecule NCAM regulates neuritogenesis by multiple mechanisms of interaction. 1646 17

Phenotyping and simple enumeration of peripheral blood mononuclear cells (PBMC) is of limited value for the assessment of many clinical states. As a preferred alternative, cell surface phenotyping may be combined with functional assays for enhanced assessment of altered cells circulating in patients. One simple, yet informative and rapid approach is to examine signaling within individual cells following brief periods of stimulation via flow cytometry. Although monocytes and lymphoid cells can be distinguished based on size, current permeabilization strategies necessary for identifying intracellular phosphorylated signaling molecules largely compromise the labeling of cell surface proteins used to distinguish individual cellular subsets. We have successfully developed conditions that allow for simultaneous detection of cell surface proteins and intracellular phosphorylated proteins in human PBMC following rapid in vitro cytokine stimulation. We analyzed permeabilized CD4, CD8, CD14, CD19, and CD56 expressing cells together with intracellular pSTAT1, pSTAT3, pSTAT5, pSTAT6, pp38 MAPK, or pERK1/2 within total PBMC. Of the permeabilizing conditions tested, 75% methanol enabled superior simultaneous detection of both cell surface and intracellular epitopes. This method enables the rapid functional analysis of subsets within complex cell mixtures and provides an opportunity for assessing abnormalities arising in the setting of acute or chronic inflammatory states.
 ...
PMID:Successful simultaneous measurement of cell membrane and cytokine induced phosphorylation pathways [CIPP] in human peripheral blood mononuclear cells. 1671 44


1 2 3 4 5 Next >>