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)

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta family of growth factors, was first identified by its ability to promote the survival of midbrain dopaminergic neurons in culture. We demonstrate that GDNF treatment of several neuroblastoma cell lines leads to dose-dependent tyrosine phosphorylation of the RET receptor and that other transforming growth factor-beta family members are not able to activate the RET receptor. GDNF treatment of neuroblastoma cells also results in increased transcription of an Elk luciferase reporter gene, suggesting that GDNF activates the mitogen-activated protein kinase signal transduction pathway.
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PMID:Glial cell line-derived neurotrophic factor signals through the RET receptor and activates mitogen-activated protein kinase. 879 76

The receptor tyrosine kinase RET functions during the development of the kidney and the enteric nervous system, yet no ligand has been identified to date. This report demonstrates that the glial cell line-derived neurotrophic factor (GDNF) activates RET, as measured by tyrosine phosphorylation of the intracellular catalytic domain. GDNF also binds RET with a dissociation constant of 8 nM, and 125I-labeled GDNF can be coimmunoprecipitated with anti-RET antibodies. In addition, exogenous GDNF stimulates both branching and proliferation of embryonic kidneys in organ culture, whereas neutralizing antibodies against GDNF inhibit branching morphogenesis. These data indicate that RET and GDNF are components of a common signaling pathway and point to a role for GDNF in kidney development.
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PMID:Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. 885 35

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait. HSCR mutations have been identified in the RET receptor tyrosine kinase, endothelin-B receptor (EDNRB) and its physiological ligand, endothelin 3 (EDN3). Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret -/-) mice. The glial cell line-derived neurotrophic factor (GDNF) is such a molecule. Recently, mice carrying two null alleles for Gdnf were shown to exhibit phenotypes remarkably similar to Ret-/- animals. We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing. We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malrotation of the gut. No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p. Our data suggest that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in enteric neurogenesis may be compensated for by other neurotrophic factors or via other pathways. However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype.
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PMID:Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. 889 68

Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. As enteric neurons are derived from the vagal neural crest, HSCR is regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder. Accordingly, segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with aganglionosis extending beyond the sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome 10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene. However, the lack of genotype-phenotype correlation, the low penetrance and the sex-dependent effect of RET mutations supported the existence of one or more modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only accounted for 50% and 15-20% of familial and sporadic HSCR patients, respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown. Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice display congenital intestinal aganglionosis and renal agenesis, a phenotype very similar to the Ret-/- mouse. These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases.
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PMID:Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. 889 69

Hirschsprung disease (HSCR) is a common congenital abnormality characterized by absence of the enteric ganglia in the hind gut. In 10-40% of HSCR cases, mutations of the RET receptor tyrosine kinase have been found. The recent identification of a multimeric RET ligand/receptor complex suggested that mutations of genes encoding other components of this complex might also occur in HSCR. To investigate this role, we examined the gene for glial cell line-derived neurotrophic factor (GDNF), the circulating ligand of the RET receptor complex, for mutations in a panel of sporadic and familial HSCR. We identified GDNF sequence variants in 2/36 HSCR patients. The first of these was a conservative change which did not affect the GDNF protein sequence. The second variant was a de novo missense mutation in a family with no history of HSCR and without mutation of the RET gene. Thus, our data are consistent with a causative role for GDNF mutations in some HSCR cases.
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PMID:De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. 896 58

Phaeochromocytomas usually occur sporadically but may also be a feature of three autosomal dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and, very rarely, type 1 neurofibromatosis. Germ-line missense mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2. In VHL, germ-line mutations in one of the three exons of the VHL tumor suppressor gene have been found in the majority of families. Whereas somatic mutations in the VHL gene have been common in sporadic renal cell carcinoma, a component cancer of VHL, somatic mutations in the RET and VHL genes together have been found in approximately 10% of sporadic phaeochromocytomas. Hence, other genes must also contribute to the pathogenesis of sporadic phaeochromocytomas. Recent data have suggested that glial cell line-derived neurotrophic factor (GDNF) is a ligand for RET and acts via a heterotetrameric receptor complex that includes GDNF receptor alpha, which provides ligand binding capabilities, and RET, which provides the signaling component. Thus, both GDNF and GDNFR-alpha are plausible candidate genes for involvement in the pathogenesis of phaeochromocytomas. To investigate the role of GDNF in sporadic phaeochromocytomas, we scanned a panel of 22 tumors. Among these samples, only a conservative sequence variant was detected in exon 2 of GDNF. No disease-associated somatic GDNF mutations or gross gene amplification were detected in these tumors, suggesting only a minor role for GDNF in the genesis of phaeochromocytomas.
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PMID:Mutation analysis of glial cell line-derived neurotrophic factor (GDNF), a ligand for the RET/GDNF receptor alpha complex, in sporadic phaeochromocytomas. 900 May 74

The RET proto-oncogene product is a receptor tyrosine kinase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), in which a novel glycosyl-phosphatidylinositol (PI)-linked protein (termed GDNFR-alpha) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-alpha in purified normal hematolymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malignancies encompassing different lineages and differentiation stages. Relatively low amounts of RET mRNA were found in early CD34+ hematopoietic progenitors, but RET transcripts appeared to increase after myelomonocytic maturation. No expression of RET was found in peripheral blood and tissue B and T lymphocytes. Analysis of human myelomonocytic cell lines was overall consistent with results obtained on purified normal cells. Accordingly, RET expression was mainly confined to acute myeloid leukemias (AMLs) displaying either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) phenotypes, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically detected in B-cell tumors, whereas, among T-cell malignancies, RET transcripts were mainly detected in cells of postthymic and mature T-cell phenotype. RET broad detection in primary tumors was not paralleled by the mutual expression of GDNFR-alpha, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-alpha transcripts, in the absence of RET mRNA, were found in normal bone marrow stromal cells (BMSC), in BM fibroblasts, and in two osteoblast cell lines previously described to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phospholipase C cleavage, GDNF efficiently bound RET-expressing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.
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PMID:Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. 910 13

Glial cell line-derived neurotrophic factor (GDNF)-dependent activation of the tyrosine kinase receptor RET is necessary for kidney and enteric neuron development, and mutations in RET are associated with human diseases. Activation of RET by GDNF has been shown to require an accessory component, GDNFR-alpha (RETL1). We report the isolation and characterization of rat and human cDNAs for a novel cell-surface associated accessory protein, RETL2, that shares 49% identity with RETL1. Both RETL1 and RETL2 can mediate GDNF dependent phosphorylation of RET, but they exhibit different patterns of expression in fetal and adult tissues. The most striking differences in expression observed were in the adult central and peripheral nervous systems. In addition, the mechanisms by which the two accessory proteins facilitate the activation of RET by GDNF are quite distinct. In vitro binding experiments with soluble forms of RET, RETL1 and RETL2 demonstrate that while RETL1 binds GDNF tightly to form a membrane-associated complex which can then interact with RET, RETL2 only forms a high affinity complex with GDNF in the presence of RET. This strong RET dependence of the binding of RETL2 to GDNF was confirmed by FACS analysis on RETL1 and RETL2 expressing cells. Together with the recent discovery of a GDNF related protein, neurturin, these data raise the possibility that RETL1 and RETL2 have distinctive roles during development and in the nervous system of the adult. RETL1 and RETL2 represent new candidate susceptibility genes and/or modifier loci for RET-associated diseases.
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PMID:Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. 917 1

Inherited predisposition to phaeochromocytoma (MIM No 171300) occurs in multiple endocrine neoplasia type 2 (MEN 2) (MIM No 171400), von Hippel-Lindau (VHL) disease (MIM No 199300), and neurofibromatosis type 1 (NF1) (MIM No 162200). In addition, familial phaeochromocytoma alone has also been reported and we and others have identified germline VHL mutations in five of six kindreds analysed previously. Germline mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, and in the VHL tumour suppressor gene cause MEN 2 and VHL disease, respectively. To further investigate the genetics of phaeochromocytoma predisposition, we analysed three groups of patients with no evidence of VHL disease, MEN 2 or NF1: Group A, eight kindreds with familial phaeochromocytoma; Group B, two patients with isolated bilateral phaeochromocytoma; and Group C, six cases of multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. Germline missense VHL mutations were identified in three of eight kindreds with familial phaeochromocytoma. A germline VHL mutation was also characterised in one of the two patients with bilateral phaeochromocytoma. No VHL or RET mutations were detected in the final group of patients with multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. The absence of germline VHL and RET gene mutations in many of these families suggested that other phaeochromoeytoma susceptibility loci may exist. Glial cell line-derived neurotrophic factor (GDNF) has been recently identified as a natural ligand for RET. Thus, it seems plausible that GDNF is a good candidate gene to play a role in phaeochromocytoma susceptibility. We searched for germline mutations in GDNF in 16 cases of familial phaeochromocytoma (groups A, B and C) and looked for evidence of somatic change in GDNF in 28 sporadic phaeochromocytomas, 12 MEN 2 phaeochromocytomas and five VHL phaeochromocytomas. No GDNF mutations were identified in patients with familial phaeochromocytoma disease, but a c277C-->T (R93W) sequence variant was identified in one of 28 sporadic tumours. This candidate mutation was identified in the germline and tumour tissue but was not present in 104 control GDNF alleles. GDNF sequence variants including R93W have been suggested previously to represent low penetrance susceptibility mutations for Hirschsprung disease and the R93W was not identified in 376 control alleles studied by others. These findings suggest that although GDNF mutations do not appear to have a major role in the pathogenesis of familial or sporadic phaeochromocytomas, allelic variation at the GDNF locus may modify phaeochromocytoma susceptibility.
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PMID:Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. 921 74

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for central dopaminergic neurons, motor neurons and several other populations of neurons in the central and peripheral nervous system. GDNF and its receptor complex of c-RET tyrosine kinase and a glycosyl-phosphatidylinositol linked protein GDNFR-alpha are of great interest due to their potential use in the therapy of Parkinson's and motoneuron diseases. We have cloned the human and rat cDNA sequences of GDNFR-beta, a new gene encoding for a 464 amino acid long homologue of GDNFR-alpha, and assign the locus of this new gene to human chromosome 8p21-22 and mouse chromosome 14D3-E1. Similarly to GDNFR-alpha, GDNFR-beta mediates GDNF-induced Ret autophosphorylation in transfected cells. By northern hybridisation we show that the transcript level of human GDNFR-beta mRNA is high in the adult brain, intestine and placenta and in fetal brain, lung and kidney. Studied by in situ hybridisation, GDNFR-beta mRNA shows in E17 rat embryo different distribution to that of GDNFR-alpha mRNA, especially, in adrenal gland, kidney and gut. In the developing nervous system, GDNFR-beta mRNA expression is restricted to certain neuronal populations, while GDNFR-alpha mRNA is widely expressed also in non-neuronal cells. The distinct tissue distribution of GDNFR-beta mRNA and its ability to mediate GDNF signal in transfected cells suggest a role in signal transduction of GDNF and, possibly, related neurotrophic factors in vivo.
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PMID:Cloning, mRNA distribution and chromosomal localisation of the gene for glial cell line-derived neurotrophic factor receptor beta, a homologue to GDNFR-alpha. 925 72


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