Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the domains of the low-affinity nerve growth factor (NGF) receptor required for appropriate signal transduction, a series of hybrid receptors were constructed that consisted of the extracellular ligand-binding domain of the human epidermal growth factor (EGF) receptor (EGFR) fused to the transmembrane and cytoplasmic domains of the human low-affinity NGF receptor (NGFR). Transfection of these chimeric receptors into rat pheochromocytoma PC12 cells resulted in appropriate cell surface expression. Biological activity mediated by the EGF-NGF chimeric receptor was assayed by the induction of neurite outgrowth in response to EGF in stably transfected cells. Furthermore, the chimeric receptor mediated nuclear signaling, as evidenced by the specific induction of transin messenger RNA, an NGF-responsive gene. Neurite outgrowth was not observed with chimeric receptors that contained the transmembrane domain from the EGFR, suggesting that the membrane-spanning region and cytoplasmic domain of the low-affinity NGFR are necessary for signal transduction.
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PMID:Chimeric NGF-EGF receptors define domains responsible for neuronal differentiation. 185 May 51

Deletion of a conserved juxtamembrane sequence (KFG) in the Trk NGF receptor resulted in impaired neurite outgrowth, somatic hypertrophy, and induction of c-fos, c-jun, and TIS1 immediate-early genes. In contrast, these receptors retained the ability to mediate NGF-promoted survival and TIS8 and TIS11 immediate-early gene induction. The mutated receptor also mediated unimpaired autophosphorylation; SHC, PLC-gamma 1, and ERK tyrosine phosphorylation; and PI-3 kinase and ERK activation. However, SNT protein tyrosine phosphorylation, which wild-type receptors mediate via a ras-independent pathway, was undetectable. These findings indicate that the KFG sequence is indispensable for activating a ras-independent NGF signaling pathway involved in promoting neuronal differentiation and highlight potential roles of non-tyrosine-containing receptor domains in growth factor signal transduction.
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PMID:Deletion of a conserved juxtamembrane sequence in Trk abolishes NGF-promoted neuritogenesis. 764 92

Two anti-nerve growth factor receptor (LNGFR or p75NGFR) antibodies, Me20.4 and Me8211, label stromal cells with dendritic features in fresh smears and in formalin-fixed, paraffin-embedded human bone marrow (BM). The LNGFR+ cells have an oval nucleus, a scanty cytoplasm with long dendrites that intermingle with the hematopoietic cells, line the abluminal side of sinus endothelial cells, and provide the scaffold for the hematopoietic marrow. At the electron microscopy level, the immunogold tag labels the body and the long branching dendrites of fibroblast-like cells with scanty cytoplasm containing mitochondria, endoplasmic reticulum, and dense bodies. The LNGFR+ cells are positive for alkaline phosphatase, reticulin, collagen III, vimentin, TE-7, and CD13 but negative for endothelial (vWF, CD34, Pal-E), neural (CD56, neurofilament) and leukocyte markers (CD45, CD68). The LNGFR+ stromal cells appear in the fetal BM before the hematopoietic activity begins, originate from the vessel adventitia, and radiate in the Bm cavity. Long-term BM culture (LTBMC) in vitro contain LNGFR+ stromal cells. We document the presence of RNA message for the low- (LNGFR) and the high-affinity NGF receptor (NTRK1) by using RT-PCR on fresh BM aspirate and on LTBMC. BM biopsies from patients with hematologic fibrogenic diseases and in cytokine-treated cancer patients are evaluated for LNGFR+ cells: the amount of stained cells is correlated with the traditional reticulin stain in cases of myelofibrosis, therapy-related myelodysplasia, leukemia, and detected an increase of stromal cells in cytokine-treated patients. The anti-LNGFR antibodies represent a specific membrane marker for the adventitial reticular cells (ARC) of the human marrow and allow precise evaluation and quantitation of this important BM microenvironment component in vivo and in vitro.
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PMID:Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitro. 768 1

The effect of constitutively expressed N-myc gene on nerve growth factor (NGF) induced neuronal differentiation was investigated. B104, a rat central nervous system-derived cell line and its N-myc gene expressing derivative lines (C6, C7) (Bernards et al., 1986), were stably transfected with the trkA proto-oncogene and independent clones for each cell line were analysed. NGF induced phosphorylation of the trkA receptor, activated a cascade of cellular intermediaries such as phospholipase C gamma 1 and ERK proteins, and stimulated c-fos gene transcription in all trkA-expressing clones. NGF-mediated neuronal differentiation was observed solely in trkA-expressing B104-derived clones and was characterized by reduced cell growth, activation of NGF-regulated genes, and downregulation of the endogenous low-affinity NGF receptor gene (gp75NGFR). No such phenotypical changes occurred in trkA-expressing C6 or C7-derived clones following NGF treatment. These results are consistent with the hypothesis that constitutive expression of N-myc inhibits exit from cell cycle and blocks neuronal cell differentiation.
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PMID:Constitutive N-myc gene expression inhibits trkA mediated neuronal differentiation. 776 Oct 93

Treatment of the rat pheochromocytoma cell line PC12 with nerve growth factor (NGF) or epidermal growth factor (EGF) is known to result in activation of Ras. In response to EGF treatment, complexes form between Sos, Grb2 and tyrosine phosphorylated Shc and/or EGF receptor. In response to NGF treatment, complexes form between Sos, Grb2 and tyrosine phosphorylated Shc. While Shc is also found bound to the activated NGF receptor, Trk, no complexes were detectable that contained both Trk and Grb2 or Sos. In streptolysin O permeabilised cells, a tyrosine phosphopeptide, EGFR-Y1068P, which binds to the SH2 domain of Grb2, totally blocks growth factor induced formation of complexes between Grb2 and Shc or EGF receptor, and also blocks activation of nucleotide exchange on Ras. At low concentrations, another tyrosine phosphopeptide, TRK-Y490P, which binds to the SH2 domain of Shc, blocks growth factor induced formation of complexes between Shc and the EGF receptor or Trk, but fails to block activation of nucleotide exchange on Ras. Higher concentrations of TRK-Y490P inhibit tyrosine phosphorylation of Shc and the formation of Shc complexes with Grb2: this results in strong inhibition of Ras activation by NGF and partial inhibition of Ras activation by EGF. These data demonstrate that the formation of a trimeric complex between tyrosine phosphorylated Shc, Grb2 and Sos is the key event in the activation of Ras in response to NGF. The binding of Sos to tyrosine phosphorylated receptor, via Grb2 may also contribute to Ras activation by EGF but not NGF, while stable complex formation between Shc and receptors is not necessary for Ras activation by either growth factor.
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PMID:Role of Shc in the activation of Ras in response to epidermal growth factor and nerve growth factor. 797 Jul 8

The insulin receptor-related receptor (IRR) has recently been identified as a member of the insulin receptor tyrosine kinase family; however, its endogenous ligand and biological function are still unknown. In contrast to the very widespread pattern of expression of the homologous insulin and IGF-I receptors, IRR demonstrates a very restricted cellular distribution. Using in situ hybridization and immunohistochemistry, we now show that the expression of this receptor is selectively concentrated in a subset of neurons where its appearance is closely associated with that of the NGF receptor TRK. IRR and TRK demonstrate synchronized patterns of coexpression in neural crest-derived sensory and sympathetic neurons and in non-neural crest basal forebrain and striatal neurons. Both appear early in the embryonic development of dorsal root and trigeminal neurons and somewhat later, near the time of birth, in sympathetic neurons. Expression of both IRR and TRK appears perinatally in basal forebrain neurons, reaching maximal levels about postnatal day 20. This association is highly selective, since TRK mRNA is not detected anywhere in the developing nervous system in the absence of coordinate IRR expression, and the same is true for IRR expression with respect to TRK. In the adult rat, the majority of TRK-positive sensory neurons still express IRR mRNA, and coexpression in sympathetic and forebrain neurons continues without evidence of diminution. These findings are consistent with a functional linkage of the IRR and TRK receptors in NGF-sensitive neurons.
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PMID:Selective coexpression of insulin receptor-related receptor (IRR) and TRK in NGF-sensitive neurons. 804 42

The expression and cellular localization of NGF receptors in the developing rat retina were investigated immunocytochemically and biochemically. In in vitro preparations of retinal neurons from neonatal rats the functional NGF receptor p140trkA was immunocytochemically detected on retrogradely labeled retinal ganglion cells (RGCs). In transverse retinal sections p140trk-immunopositive cells were localized exclusively at the level of the RGC layer. Affinity labeling with 125I-NGF, chemical cross-linking, and immunoprecipitation with anti-NGF antibodies revealed the presence of three complexes which migrate on SDS-PAGE at approximately 90, 95, and 150 kDa. The bands at 90 and 95 kDa correspond to the so-called low affinity NGF receptor p75NGFR. Western blotting experiments using anti-TRK antibodies revealed that the slowest migrating band (150 kDa), which is not immunoprecipitated by monoclonal antibodies to p75NGFR, corresponds to p140trkA. The presence of the functional NGF receptor on RGCs provides the molecular explanation for the reported sensitivity of these cells to the biological action of NGF.
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PMID:Developing rat retinal ganglion cells express the functional NGF receptor p140trkA. 836 54

Schwann cells are one of the principal components of the peripheral nervous system. They play a crucial role in nerve regeneration and can be used clinically in the repair of injured nerves. We have established serum-free, defined culture conditions that rapidly expand adult human Schwann cells without fibroblast growth. We find that Gas6, a ligand for the Axl and Rse/Tyro3 receptor protein tyrosine kinase family, stimulates human Schwann cell growth, increasing both cell number and thymidine incorporation. Gas6 has synergistic effects with the other known human Schwann cell mitogens, heregulin/glial growth factor and forskolin. Addition of Gas6 causes phosphorylation of Axl and Rse/Tyro3 simultaneously and results in ERK-2 activation. A combination of Gas6 with heregulin and forskolin, on a defined background, supports maximal Schwann cell proliferation, while preserving the typical Schwann cell morphology and expression of the Schwann cell markers S-100, glial fibrillary acidic protein, and low-affinity nerve growth factor receptor. Gas6 mRNA is present in both spinal motor neurons and large neurons of the dorsal root ganglia, and neural injury has been reported to upregulate Rse/Axl in the schwann cell. This is the first demonstration of a potentially important biological role for the human Gas6/Rse-Axl system.
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PMID:Identification of Gas6 as a growth factor for human Schwann cells. 860 45

Nerve growth factor (NGF) is of major importance for the survival, development and maintenance of peripheral sympathetic and central neuronal tissue. Most of the cellular effects are mediated by binding to their high-affinity receptor c-TRK, a transmembrane receptor tyrosine kinase. C-TRK protein has been detected in neuronal tissue and also in mast cells, monocytes and some haemopoletic progenitor cells. Here we report c-TRK gene expression in myeloid leukaemic cell lines (HEL, K562 and KG-1) and for the first time in the primary leukaemic cells of 44% (n = 59) of patients with acute myelogenous leukaemia (AML). Moreover, in the human promyelocytic cell line HL-60, c-TRK expression was inducible by differentiation induction with tetradecanoyl-phorbol 13-acetate (TPA). In c-TRK gene-expressing cells the transmembrane receptor tyrosine kinase was detectable by Western blotting and by in vitro kinase assay. In the AML group, c-TRK expression was not correlated to the FAB-classified morphology or any other clinical parameter. In all cases tested we could not detect NGF mRNA by means of reverse transcriptase PCR, excluding an autocrine loop involving the TRK/NGF receptor-ligand system in leukaemogenesis. Our results show another example of possible communication between neuronal and haemopoietic tissue. However, we still lack positive evidence of a c-TRK function in haemopoiesis.
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PMID:Expression of the nerve growth factor receptor c-TRK in human myeloid leukaemia cells. 885 45

Hereditary sensory neuropathy Type II (HSN II) is an autosomal recessive disorder characterized by the loss of peripheral sensory modalities in individuals with otherwise normal development. Patients with HSN II often have chronic ulceration of the fingers and toes, autoamputation of the distal phalanges, and neuropathic joint degeneration associated with loss of pain sensation. Recent descriptions of a similar phenotype in mice carrying a targeted mutation in the low affinity nerve growth factor receptor, p75NGFR, suggested the possibility that mutations in this gene or other members of the nerve growth factor (NGF) family of genes and their receptors might be responsible for this human disorder. In this study candidate genes were evaluated by their inheritance pattern in two sisters affected with HSN II, their unaffected sister and mother in a consanguineous family. The segregation of polymorphic alleles at and around loci for p75NGFR, TRKA, TRKB, BDNF, and familial dysautonomia (another hereditary sensory neuropathy having features in common with HSN II) virtually excluded these genes as the cause of HSN II in this family. Further evaluation of loci for other neurotrophic factors and their receptors, which will be possible when mapping information on their loci becomes available, may permit the identification of the gene responsible for HSN II.
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PMID:Exclusion of p75NGFR and other candidate genes in a family with hereditary sensory neuropathy type II. 927 17


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