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)

Nerve growth factor (NGF) binds to two structurally unrelated transmembrane proteins on the surface of PC-12 cells, a 75-kDa glycoprotein with a short cytoplasmic sequence, and the trk protooncogene (pp140c-trk), a protein tyrosine kinase activated by NGF. Immediately after binding to cells, NGF induces changes in serine/threonine phosphorylation of several proteins. We have explored the relative roles of these two NGF binding proteins in mediating the activation of two intracellular kinases that may be responsible for some of these phosphorylations. The raf-1 protooncogene is a serine/threonine kinase activated by several growth factors and oncogenic proteins. Treatment of PC-12 cells with NGF increases the serine and threonine phosphorylation of raf-1 in an anti-raf-1 immunoprecipitate kinase assay. This increased phosphorylation observed in vitro is dose-dependent and transient and is accompanied by the NGF-dependent shift in the mobility of immunoblotted raf-1 on SDS sodium dodecyl sulfate-polyacrylamide gel electrophoresis, an effect thought to reflect phosphorylation. NGF-dependent activation of raf-1 is not dependent on protein kinase C, since prolonged exposure to phorbol esters under conditions that cause down-regulation of cellular protein kinase C activity has no effect on the NGF response. Expression of pp140c-trk in 3T3 fibroblasts (3T3-c-trk), as evidenced by cross-linking of 125I-NGF to the 140-kDa protein, permits the NGF-dependent activation of raf-1 kinase, detected in the immunoprecipitate kinase assay, anti-raf immunoblot shift on gel electrophoresis, and incorporation of [32P]orthophosphate into the raf-1 protein. The concentration dependence of raf-1 activation is identical in 3T3-c-trk and PC-12 cells, despite the absence of the 75-kDa NGF binding protein in 3T3-c-trk cells. NGF is without effect in untransfected 3T3 cells or in Chinese hamster ovary cells overexpressing p75, although raf-1 is present in these cells. Similarly, the NGF-dependent activation of mitogen-activated protein (MAP) kinase is detected in 3T3-c-trk cells, but not in untransfected 3T3 or Chinese hamster ovary cells overexpressing p75. As described for raf-1 activation, the NGF dose responses for MAP kinase activation in 3T3-c-trk and PC-12 cells are virtually superimposable. These data indicate that the activation of these two serine/threonine kinases by NGF is mediated solely by binding to and activating the pp140c-trk receptor.
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PMID:Nerve growth factor stimulates the activities of the raf-1 and the mitogen-activated protein kinases via the trk protooncogene. 132 11

The pleiotropic cytokine tumor necrosis factor-alpha (TNF alpha) controls the expression of multiple gene products in macrophages and plays an important role in host defense. TNF alpha is recognized by the receptors, CD120a (p55) and CD120b (p75). Ligation of CD120a (p55) by TNF alpha or by anti-receptor agonistic antibodies initiates signal transduction leading to the activation of mitogen-activated protein kinases (MAPKs) (p42mapk/erk2 and p44mapk/erk1). Phosphorylation and activation of MAPK are mediated by MAPK kinase (MEK), a family of Thr/Tyr kinases. In this study, we investigated the preferential involvement of the MEK isoforms MEK1 and MEK2 in the activation of p42mapk/erk2 in mouse macrophages stimulated with TNF alpha. Exposure of macrophages to TNF alpha stimulated a time-dependent increase in the activity of MEK1 as measured by an in vitro kinase assay using kinase-inactive p42mapk/erk2 (rMAPKkd) as substrate in the presence of gamma-[32P]ATP. Maximal activation of MEK1 was detected at 10 min poststimulation and coincided with maximal transphosphorylation of Tyr and Thr residues of rMAPKkd. By contrast, there was no evidence of MEK2 activation in macrophages in response to TNF alpha. These data suggest that MEK1 is the preferred substrate for MEK kinase, the upstream kinase implicated in activation of the MAPK pathway in macrophages by TNF alpha.
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PMID:Preferential involvement of MEK1 in the tumor necrosis factor-alpha-induced activation of p42mapk/erk2 in mouse macrophages. 749 90

To dissect tumor necrosis factor receptor (Tnfr)-1 (CD120a) and Tnfr2 (CD120b)-dependent signal transduction pathways, primary fibroblasts isolated from inguinal adipose tissue of wild type (wt), tnfr1(o), tnfr2(o), and tnfr1(o)/tnfr2(o) mice were studied. The mitogen-activated protein kinases Erk1 and Erk2 were found to be tyrosine-phosphorylated and activated by Tnf treatment in all wt, tnfr1(o), and tnfr2(o) fibroblasts; the activation was down-regulated 60 min after the start of steady state Tnf treatment. Distinct kinetics of Erk1 and Erk2 activation were detected; the Tnfr1-mediated activation of Erk1 and Erk2 started more slowly and persisted for more prolonged times as compared with Tnfr2 activation. Raf-1, Raf-B, Mek-1, Mek kinase, and p90(rsk) kinases were also shown to be activated independently in a distinct time-dependent pattern through the two Tnf receptors. In addition, both Tnfr1 and Tnfr2 mediated independently the activation of the transcription factor Ap-1 albeit with parallel activation kinetics. In contrast, Tnfr1 exclusively mediated activation of NF-kappaB and fibroblast proliferation; however, Tnfr2 enhanced proliferation triggered through Tnfr1. These findings indicate distinct but also overlapping roles of Tnfr1 and Tnfr2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors.
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PMID:Tumor necrosis factor receptors (Tnfr) in mouse fibroblasts deficient in Tnfr1 or Tnfr2 are signaling competent and activate the mitogen-activated protein kinase pathway with differential kinetics. 891 Apr 23

Nerve growth factor (NGF) can influence mast cell development and function in murine rodents by interacting with its receptors on mast cells. We now report the identification of mRNA transcripts of full-length tyrosine kinase-containing trkA, trkB, and trkC neurotrophin receptor genes in HMC-1 human mast cell leukemia cells. Although HMC-1 cells lacked p75 mRNA, they expressed transcripts for the exon-lacking splice variant of trkA (trkAI), truncated trkB (trkB.T1), and truncated trkC. By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains. NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen-activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional. Highly purified populations of human lung mast cells expressed mRNAs for trkA, trkB and trkC, whereas preparations of human umbilical cord blood-derived mast cells expressed mRNAs for trkA and trkC, but not trkB. Moreover, preparations of human umbilical cord blood-derived immature mast cells not only expressed mRNA transcript and protein for TrkA, but exhibited significantly higher numbers of chymase-positive cells after the addition of NGF to their culture medium for 3 weeks. In addition, HMC-1 cells expressed mRNAs for NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), the cognate ligands for TrkA, TrkB, and TrkC, whereas NGF and BDNF transcripts were detectable in human umbilical cord blood mast cell preparations. Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans. Our studies also raise the possibility that human mast cells may represent a potential source for neurotrophins.
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PMID:Expression of functional TrkA receptor tyrosine kinase in the HMC-1 human mast cell line and in human mast cells. 929 13

Adult rat chromaffin cells may proliferate or extend neurites when stimulated by nerve growth factor (NGF) but their response is predominantly proliferative, making them a unique model for studying how mitogenic specificity is achieved. We examined contributions of the NGF receptors trk and p75 and of the major NGF signaling pathways to proliferation versus neurite outgrowth. The type of initial NGF response does not correlate with intensity of immunoreactivity for trk or p75. However, proliferation is initiated at lower NGF concentrations than neurite outgrowth, suggesting that it requires a less intense signal. Mitogenic cooperativity between receptors at low NGF concentrations is suggested by inhibitory effects of p75-blocking antibodies, but responses to trk-agonist antibody indicate that trk activation alone can induce proliferation. NGF-induced phosphorylation of ras-mediated mitogen-activated protein kinases (MAPK) Erk1 and Erk2 is as prolonged in normal chromaffin cells as in PC12 cells, where NGF is neuritogenic. Trk-agonist antibody, which is as mitogenic as NGF but less neuritogenic, causes equally prolonged but less intense ERK phosphorylation. The MAPK kinase(MEK-1) inhibitor PD98059 partially inhibits Erk phosphorylation and does not inhibit chromaffin cell proliferation, while depolarization selectively inhibits proliferation without blocking Erk phosphorylation. Proliferation is markedly reduced by the phosphoinositol-3 (PI-3) kinase inhibitor LY294002 while downregulation of protein kinase C (PKC) causes no change. These findings suggest that low-level, rather than short-duration, stimulation of NGF signaling pathways causes NGF to be mitogenic. Ras-mediated MAPK activation may be more critical in neurite outgrowth than in proliferation and PI-3 kinase may be the major mitogenic determinant.
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PMID:Nerve growth factor receptor signaling in proliferation of normal adult rat chromaffin cells. 993 50

Accumulating evidence suggests that the neurotrophin receptors, Trks and p75, play distinct roles in regulating cells survival and death, with Trks important for cell survival, and p75 acting to induce cell death. Here, we provide evidence that, in neuronal cultures from rat cerebral cortex, nerve growth factor (NGF) exerts neuroprotective actions via p75. Incubating cultures with NGF for 1-24 h protected cortical neurons from delayed cytotoxicity induced by brief exposure to glutamate. Delayed neurotoxicity induced by a calcium ionophore, ionomycin, or nitric oxide (NO) donors such as S-nitrosocysteine (SNOC) and 3-morpholinosydnonimine (SIN-1), was also attenuated by pretreatment with NGF. RT-PCR analysis revealed the presence of p75 and trkB transcripts in cortical cultures, but did not detect transcripts of trkA, a high-affinity receptor for NGF. Brain-derived neurotrophic factor (BDNF), but not NGF, induced tyrosine phosphorylation of Trks, indicating that NGF does not activate Trks in cortical neurons. Concurrent application of anti-p75 neutralizing antibody markedly reduced the neuroprotective effect of NGF, but resulted in only a modest reduction of that of BDNF. BDNF-induced neuroprotection, but not NGF-induced neuroprotection, was inhibited by a protein synthesis inhibitor cycloheximide. Distinct signaling pathways mobilized by NGF and BDNF were also revealed in that NGF but not BDNF stimulated significant production of ceramides, whereas BDNF but not NGF caused persistent activation of mitogen-activated protein kinases. These results indicate that, although NGF and BDNF both protect cortical neurons from excitotoxicity, the mechanisms involved in their effects are totally different. The present results are, to our knowledge, the first to demonstrate the principal involvement of p75 in cytoprotective actions of neurotrophins.
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PMID:p75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures. 1067 54

In this study, we examined the expression of nerve growth factor (NGF) and its receptors in mouse macrophages and the mechanisms involved in the effect of NGF on tumor necrosis factor (TNF)-alpha production. Macrophages expressed NGF and the NGF receptors TrkA and p75. Treatment of J744 cells or peritoneal macrophages with NGF induced a large increase in the production of TNF-alpha. In addition, NGF induced the secretion of nitric oxide in interferon-gamma-treated J774 cells or lipopolysaccharide-treated peritoneal macrophages. The induction of TNF-alpha production by NGF was blocked by K252a, an inhibitor of the TrkA receptor. NGF induced phosphorylation and activation of extracellular signal-regulated kinase, Erk1/Erk2 and c-Jun amino-terminal kinase, whereas it did not induce phosphorylation of p38 mitogen-activated protein kinase. Inhibition of the MAP kinase-Erk kinase pathway with PD 098059 decreased the secretion of TNF-alpha by NGF. Our results suggest that NGF has an important role in the activation of macrophages during inflammatory responses via activation of mitogen-activated protein kinases.
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PMID:Nerve growth factor regulates TNF-alpha production in mouse macrophages via MAP kinase activation. 1140 90

Nerve growth factor (NGF) has been implicated as both an inhibitor and an inducer of apoptosis. Binding of NGF to its TrkA receptor is generally considered to have an antiapoptotic effect. However, neuroblastomas that overexpress TrkA have a good prognosis and frequently regress by apoptosis either spontaneously or after chemotherapeutic treatment, whereas those that express little or no TrkA are lethal in 80-95% of patients, despite maximal therapy. We now report that NGF treatment of PC12 neural crest tumor cells trkA-transfected to express TrkA at levels analogous to those seen in "good prognosis" neuroblastomas results in cell death; similar treatment of native cells that express TrkA at levels similar to those of "poor prognosis" neuroblastomas has no effect on cell survival. Morphological and biochemical studies indicate that NGF induces atypical apoptosis that is abrogated by the tyrosine kinase inhibitor K252alpha, but not by an inhibitor of NGF-p75 binding, in trkA-transfected PC12 cells. Differential activation of the TrkA-phosphorylated mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase 1-phosphorylated ERK-phosphorylated cAMP-responsive element-binding protein and TrkA-phosphorylated MAP/ERK kinase 3/6-phosphorylated p38 MAP signal transduction pathways, also suppressible by K252alpha, occurs in the two cell types. This difference may mediate their differential survival after exposure to NGF.
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PMID:TrkA as a life and death receptor: receptor dose as a mediator of function. 1220 32

The role of the common neurotrophin receptor p75 (p75NTR) in neuronal survival and cell death remains controversial. On the one hand, p75NTR provides a positive modulatory influence on nerve growth factor (NGF) signaling through the high affinity neurotrophin receptor TrkA, and hence increases NGF survival signaling. However, p75NTR may also signal independently of TrkA, causing cell death or cell survival, depending on the cell type and stage of development. Here we demonstrate that TrkA is expressed in primary cultures of hippocampal neurons and is activated by NGF within 10 min of exposure. In primary hippocampal cultures neuroprotection by NGF against glutamate toxicity was mediated by NF-kappaB and accompanied by an increased expression of neuroprotective NF-kappaB target genes Bcl-2 and Bcl-xl. In mouse hippocampal cells lacking p75NTR (p75NTR-/-) activation of TrkA by NGF was not detectable. Moreover, neuroprotection by NGF against glutamate toxicity was abolished in p75NTR-/- neurons, and the expression of bcl-2 and bcl-xl was markedly reduced as compared to wildtype cells. NGF increased TrkA phosphorylation in hippocampal neurons and provided protection that required phosphoinositol-3-phosphate (PI3)-kinase activity and Akt phosphorylation, whereas the mitogen-activated protein kinases (MAPK), extracellular-regulated kinases (Erk) 1/2, were not involved. P75NTR signaling independent of TrkA, such as increased neutral sphingomyelinase (NSMase) activity causing enhanced levels of ceramide, were not detected after exposure of hippocampal neurons to NGF. Interestingly, inhibition of sphingosine-kinase blocked the neuroprotective effect of NGF, suggesting that sphingosine-1-phosphate was also involved in NGF-mediated survival in our cultured hippocampal neurons. Overall, our results indicate an essential role for p75NTR in supporting NGF-triggered TrkA signaling pathways mediating neuronal survival in hippocampal neurons.
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PMID:Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75. 1245 82

The role played by PDGF in testis morphogenesis is still incompletely understood. The present study investigates the expression and potential role of platelet-derived growth factor-BB (PDGF-BB) and its receptor, PDGF receptor beta (PDGFR-beta), during mouse testis cord formation, and the possibility that the growth factor may be involved in the migration to the gonad of mesenchymal cells of mesonephric origin. Studies from this laboratory have previously shown that mesenchymal cells that migrate from the mesonephros into the gonad, to form peritubular myoid cells and most of the intertubular cells, can be identified by the presence on their surface of the p75 neurotrophin receptor (p75NTR), and can be isolated to near-purity by immunomagnetic selection with anti-p75NTR antibody. We show here that mesonephric p75NTR(+) cells also bear the PDGFR-beta, and are able to migrate and proliferate in vitro in response to PDGF-BB. PDGF-BB is expressed at higher levels in male than female developing gonads, suggesting a role for this factor in testis development. Such a role is further supported by the observation that addition of PDGF-BB to serum-free medium is sufficient to allow organ-cultured male 11.5 days post-coitum urogenital ridges to form testis cords. Finally, we show that mesonephric cell motility and growth induced by exposure to PDGF-BB involve mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3 kinase (PI3-K) pathways, as MAPK inhibitor U0126 and PI3K inhibitor Ly294002 inhibit migration and proliferation in vitro assays. The present findings support the hypothesis that the PDGF/PDGFR system plays a key role in testis morphogenesis in the mouse embryo.
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PMID:Expression and role of PDGF-BB and PDGFR-beta during testis morphogenesis in the mouse embryo. 1499 38


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