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)

Sympathetic axons use blood vessels as an intermediate path to reach their final target tissues. The initial contact between differentiating sympathetic neurons and blood vessels occurs following the primary sympathetic chain formation, where precursors of sympathetic neurons migrate and project axons along or toward blood vessels. We demonstrate that, in Ret-deficient mice, neuronal precursors throughout the entire sympathetic nervous system fail to migrate and project axons properly. These primary deficits lead to mis-routing of sympathetic nerve trunks and accelerated cell death of sympathetic neurons later in development. Artemin is expressed in blood vessels during periods of early sympathetic differentiation, and can promote and attract axonal growth of the sympathetic ganglion in vitro. This analysis identifies RET and artemin as central regulators of early sympathetic innervation.
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PMID:RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. 1164 Dec 20

The catalytic and signaling activities of RET, a tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), are controlled by the autophosphorylation of several tyrosine residues in the RET cytoplasmic domain. To analyze the phosphorylation state of individual tyrosines, we generated antibodies recognizing specific phosphotyrosine sites involved in the catalytic (Tyr(905)) and downstream signaling (Tyr(1015), Tyr(1062), and Tyr(1096)) activities of this receptor. Stimulation with GDNF induced coordinated phosphorylation of the 4 tyrosine residues in neuronal cell lines and in primary cultures of sympathetic neurons isolated from rat superior cervical ganglia. Neurturin and artemin, two other members of the GDNF ligand family, also induced synchronized phosphorylation of RET tyrosines with kinetics comparable to those observed with GDNF. Tyrosine phosphorylation was maximal 15 min after ligand stimulation, decaying thereafter with similar kinetics in all 4 residues. Co-stimulation with a soluble form of the GFRalpha1 co-receptor potentiated ligand-dependent phosphorylation of different intracellular tyrosines to a similar extent and increased the survival of superior cervical ganglion neurons compared with treatment with GDNF alone. In vivo, high levels of phosphorylated Tyr(905), Tyr(1015), and Tyr(1062) were detected in embryonic mouse dorsal root ganglia, with a sharp decline at early postnatal stages. Protein transduction of anti-Tyr(P)(1062) antibodies into cultured cells reduced activation of MAPKs ERK1 and ERK2 and the AKT kinase in response to GDNF and diminished GDNF-dependent neuronal differentiation and survival of embryonic sensory neurons from the nodose ganglion. These results demonstrate synchronized utilization of individual RET tyrosine residues in neurons in vivo and reveal an important role for RET Tyr(1062) in mediating neuronal survival by GDNF.
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PMID:Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. 1171 47

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.
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PMID:Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. 1267 85

Olfactory ensheathing cells (OEC) constitute a specialized population of glia that accompany primary olfactory axons and have been reported to facilitate axonal regeneration after spinal cord injury in vivo. In the present report we describe OEC neurotrophic factor expression and neurotrophic properties of OECs in vitro. Investigation of the rat olfactory system during development and adulthood by radioactive in situ hybridization revealed positive labeling in the olfactory nerve layer for the neurotrophic molecules S-100beta, CNTF, BMP-7/OP-1, and artemin, as well as for the neurotrophic factor receptors RET and TrkC. Ribonuclease protection assay of cultured OEC revealed expression of NGF, BDNF, GDNF, and CNTF mRNA, while NT3 and NT4 mRNA were not detectable. In vitro bioassays of neurotrophic activity involved coculturing of adult OEC with embryonic chick ganglia and demonstrated increased neurite outgrowth from sympathetic, ciliary, and Remak's ganglia. However, when culturing the ganglia with OEC-conditioned medium, neurite outgrowth was not stimulated to any detectable extent. Our results suggest that the neurotrophic properties of OEC may involve secretion of neurotrophic molecules but that cellular interactions are crucial.
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PMID:Neurotrophic properties of olfactory ensheathing glia. 1268 30

Glial-cell-line-derived neurotrophic factor (GDNF) was originally identified as a survival factor for midbrain dopaminergic neurons. GDNF and related ligands, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), maintain several neuronal populations in the central nervous systems, including midbrain dopamine neurons and motoneurons. In addition, GDNF, NRTN and ARTN support the survival and regulate the differentiation of many peripheral neurons, including sympathetic, parasympathetic, sensory and enteric neurons. GDNF has further critical roles outside the nervous system in the regulation of kidney morphogenesis and spermatogenesis. GDNF family ligands bind to specific GDNF family receptor alpha (GFRalpha) proteins, all of which form receptor complexes and signal through the RET receptor tyrosine kinase. The biology of GDNF signalling is much more complex than originally assumed. The neurotrophic effect of GDNF, except in motoneurons, requires the presence of transforming growth factor beta, which activates the transport of GFRalpha1 to the cell membrane. GDNF can also signal RET independently through GFR1alpha. Upon ligand binding, GDNF in complex with GFRalpha1 may interact with heparan sulphate glycosaminoglycans to activate the Met receptor tyrosine kinase through cytoplasmic Src-family kinases. GDNF family ligands also signal through the neural cell adhesion molecule NCAM. In cells lacking RET, GDNF binds with high affinity to the NCAM and GFRalpha1 complex, which activates Fyn and FAK.
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PMID:Novel functions and signalling pathways for GDNF. 1295 54

Artemin (ART) signals through the GFR alpha-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesions including fusion of adrenal medullae with adjacent paraganglia, adrenal medullary dysplasia, and marked enlargement of sympathetic (superior cervical and sympathetic chain ganglia) and parasympathetic (enteric, pelvic) ganglia. Changes began by gestational day 12.5 and formed progressively larger masses during adulthood. Art supplementation in wild type adult mice by administering recombinant protein or an Art-bearing retroviral vector resulted in hyperplasia or neuronal metaplasia at the adrenal corticomedullary junction. Expression data revealed that Gfr alpha-3 is expressed during development in the adrenal medulla, sensory and autonomic ganglia and their projections, while Art is found in contiguous mesenchymal domains (especially skeleton) and in certain nerves. Intrathecal Art therapy did not reduce hypalgesia in rats following nerve ligation. These data (1) confirm that ART acts as a differentiation factor for autonomic (chiefly sympathoadrenal but also parasympathetic) neurons, (2) suggest a role for ART overexpression in the genesis of pheochromocytomas and paragangliomas, and (3) indicate that ART is not a suitable therapy for peripheral neuropathy.
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PMID:The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction. 1520 70

The carotid body is a neural crest-derived neuroendocrine organ that detects the oxygen level in blood and regulates ventilation. Unlike many other neural crest derivatives, the trophic factors mediating survival and differentiation of neuroendocrine cells of the carotid body are unknown. Given that many neural crest derivatives rely on the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) for survival and function, we undertook an analysis of the carotid body as a potential site of GFL action. RET and GDNF family receptor alphas (GFRalpha) 1-3 are expressed in the developing carotid body as detected by RT-PCR and immunocytochemistry. mRNA for GDNF, and artemin (ARTN) were also present. In vitro, treatment with GDNF, neurturin (NRTN), or ARTN, individually or in combination, produced an increase in the number and length of processes of the Type-I glomus cells of the carotid body [embryonic day-17 (E17) rats]. However, GFLs alone or in combination had no effect on glomus cell survival in either postnatal day-1 (P1) or E17 carotid body cultures. These results suggest that one or more GFLs may have a role in carotid body function. In addition, the results of this study suggest that endogenous or exogenous GFLs may enhance target innervation by carotid body transplants.
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PMID:Expression and function of GDNF family ligands and receptors in the carotid body. 1562 63

To clarify whether glial cell line-derived neurotrophic factor (GDNF) receptor alpha-1 (GFRalpha1), the glycosylphosphatidylinositol (GPI)-linked coreceptor for GDNF, is also a functional coreceptor for artemin (ART), we have studied receptor binding, signaling, and neuronal survival. In cell-free binding studies, GFRalpha1-Ig displayed strong preferential binding to GDNF, though in the presence of soluble RET, weak binding to ART could also be detected. However, using GFRalpha1-transfected NB41A3 cells, ART showed no detectable competition against the binding of (125)I-labeled GDNF. Moreover, ART failed to induce phosphorylation of extracellular signal-related kinase (ERK) and Akt in these cells and was >10(4)-fold less potent than GDNF in stimulating RET phosphorylation. When rat primary dorsal root ganglion (DRG) neurons were used, only the survival promoting activity of GDNF and not that of ART was blocked by an anti-GFRalpha1 antibody. These results indicate that although ART can interact weakly with soluble GFRalpha1 constructs under certain circumstances in vitro, in cell-based functional assays GFRalpha1 is at least 10 000-fold selective for GDNF over ART. The extremely high selectivity of GFRalpha1 for GDNF over ART and the low reactivity of ART for this receptor suggest that GFRalpha1 is not likely to be a functional coreceptor for ART in vivo.
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PMID:Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-1 (GFR alpha 1) is highly selective for GDNF versus artemin. 1570 67

Glial-derived neurotrophic factor (GDNF), neurturin (NRTN), persephin (PSPN), and artemin (ARTN) are a group of proteins belonging to the GDNF family ligands (GFLs). GDNF, NRTN, and ARTN support the survival of central, peripheral, and autonomic neuron populations, while PSPN supports the survival of only several central neuron populations. A common receptor, RET, modulates the action of this family and a co-receptor, GFRalpha, determines RET ligand specificity. GDNF and NRTN appear to be essential for enteric nervous system (ENS) development in mammals, zebrafish, and other teleostean species. GFLs are also essential for the maintenance and plasticity of adult mammalian ENS. In this study, the distribution pattern of GFLs in the intestine of five adult fish (bass, gilt-head, scorpionfish, trout, and zebrafish) was evaluated by immunochemical and immunocytochemical analysis. The results demonstrated the presence of GDNF, NRTN, and ARTN in the gut of all species studied. They appeared to be spread in the ENS and/or endocrine cells of the intestine. These findings suggest that the presence of GFLs in fish gut is not only limited to developmental period, but could be also involved in the enteric physiology of adult species.
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PMID:GDNF family ligand immunoreactivity in the gut of teleostean fish. 1619 78

The c-ret protooncogene, RET, encodes a receptor tyrosine kinase. RET is activated by members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands, which include GDNF, neurturin, artemin, and persephin. The ligands bind RET through GDNF family receptor alpha, termed GFRalpha1-4. Despite the importance of RET signaling in the development of the enteric nervous system and the kidney, the differential signaling mechanisms between RET ligands are poorly established. It has been suggested that signal specificity is achieved through binding of the ligand to its preferred GFRalpha. To compare the signaling profiles of GDNF and neurturin, we have identified a cell line, NG108-15, which endogenously expresses RET and GFRalpha1 but not GFRalpha2-4. Immunoblot data showed that GDNF caused a transient activation, whereas neurturin caused a sustained activation, of both p44/p42 MAP kinases and PLCgamma. Under serum starvation, NG108-15 cells differentiate and form neurites. Neurturin but not GDNF stimulated neurite outgrowth, which could be blocked by the selective PLC inhibitor U73122. On the other hand, GDNF but not neurturin promoted cell survival, and this could be blocked by the p44/p42 MAP kinase inhibitor PD98059. Our findings not only show the differential signaling of GDNF and neurturin but also suggest that this can be achieved through binding to the same GFRalpha subtype, leading to distinct biological responses.
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PMID:Differential effects of glial cell line-derived neurotrophic factor and neurturin in RET/GFRalpha1-expressing cells. 1629 36


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