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)

Gain-of-function mutations of ret receptor tyrosine kinase, the signaling receptor for glial cell line-derived neurotrophic factor, cause sporadic thyroid and adrenal malignancies as well as endocrine cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma. Loss-of-function mutations of ret cause Hirschsprung's disease (HSCR) or colonic aganglionosis. In 20-30% of families with a mutation at residues 609, 611, 618, or 620 of RET, MEN 2A and familial medullary thyroid carcinoma cosegregate with HSCR. These mutations constitutively activate RET due to aberrant disulfide homodimerization and diminish the level of RET at the plasma membrane. It is not known how these mutations simultaneously lead to both gain- and loss-of-function RET-associated diseases. We provide an explanation for the dual phenotypic Janus mutation at Cys620 of RET. In Madin-Darby canine kidney (MDCK) cells, the Janus mutation impairs the glial cell line-derived neurotrophic factor-induced effects of RET on cell migration, differentiation, and survival but simultaneously promotes rapid cell proliferation.
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PMID:Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease. 1471 28

Glial cell line-derived neurotrophic factor (GDNF), a ligand of RET tyrosine kinase, and its family ligands promote the survival and differentiation of a variety of neurons. Gene ablation studies have revealed that the GDNF-RET receptor system is essential for the development of kidney and peripheral neurons, including sympathetic, parasympathetic and enteric neurons. RET can activate various signaling pathways such as RAS/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. These signaling pathways are activated via binding of adaptor proteins to intracellular tyrosine residues of RET phosphorylated by its own kinase activity. The RET is profoundly involved in the development of several human neuroendocrine diseases. The constitutive activation of the RET by somatic rearrangement with other partner genes or germ-line mutations causes a considerable population of human papillary thyroid carcinomas or multiple endocrine neoplasia (MEN) type 2A and 2B, respectively, whereas the dysfunction of RET by germ-line missense and/or nonsense mutations causes Hirschsprung's disease. Biological properties of mutant RET protein determine the disease phenotype. For example, the MEN 2B mutation alters the substrate specificity of RET tyrosine kinase and RET carrying the MEN 2B mutation hereby induces the different set of genes from that carrying the MEN 2A mutation. In this review, we describe the current knowledge about the molecular mechanism of RET activation in human neuroendocrine tumors as well as the physiological roles and signal transduction of RET tyrosine kinase.
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PMID:RET and neuroendocrine tumors. 1501 19

Glial cell line-derived neurotrophic factor (GDNF) binds to the GDNF family co-receptor alpha1 (GFRalpha1) and activates RET receptor tyrosine kinase. GFRalpha1 has a putative domain structure of three homologous cysteine-rich domains, where domains 2 and 3 make up a central domain responsible for GDNF binding. We report here the 1.8 A crystal structure of GFRalpha1 domain 3 showing a new protein fold. It is an all-alpha five-helix bundle with five disulfide bridges. The structure was used to model the homologous domain 2, the other half of the GDNF-binding fragment, and to construct the first structural model of the GDNF-GFRalpha1 interaction. Using site-directed mutagenesis, we identified closely spaced residues, Phe213, Arg224, Arg225 and Ile229, comprising a putative GDNF-binding surface. Mutating each one of them had slightly different effects on GDNF binding and RET phosphorylation. In addition, the R217E mutant bound GDNF equally well in the presence and absence of RET. Arg217 may thus be involved in the allosteric properties of GFRalpha1 or in binding RET.
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PMID:The structure of GFRalpha1 domain 3 reveals new insights into GDNF binding and RET activation. 1504 50

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival agent for neurons, however, its effect on A beta-evoked neuronal death has not been examined. We show that the injection of A beta into New Zealand white rabbit brain activates the endoplasmic reticulum (ER) chaperones, grp 78 and grp 94, and the transcription factor, gadd 153. These effects correlate with the activation of JNK and ERK as well as of microglia and with the phosphorylation of tau protein. Treatment with GDNF inhibits the activation of gadd 153, reduces the phosphorylation of JNK, abolishes the phosphorylation of ERK, prevents microglial activation, greatly reduces apoptotic cells, and does not affect the phosphorylation of tau. Our data suggest that the tau hyperphosphorylation and apoptosis triggered by A beta are two independent events, and that the neuroprotective effect of GDNF against A beta may result either directly by the inhibition of ER stress or indirectly through the inhibition of JNK and ERK activation.
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PMID:GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. 1519 98

Collapsin response mediator protein-2 (CRMP-2) is a mammalian homologue of UNC-33 of Caenorhabditis elegans. Mutations of CRMP-2 result in abnormal axon termination. Recently, it was demonstrated that CRMP-2 binds to tubulin heterodimers to promote microtubule assembly that is critical for axonal differentiation and growth during development. Here we show that glial cell line-derived neurotrophic factor (GDNF) enhances CRMP-2 expression in TGW human neuroblastoma cells via activation of RET receptor tyrosine kinase. GDNF-mediated CRMP-2 expression was regulated mainly by the extracellular regulated kinase (ERK) pathway, but was independent of activation of phosphatidylinositol 3-kinase and Src family kinases. Analysis of the promoter region of the CRMP-2 gene revealed that the region 214-48 bp upstream of the transcriptional start site is important for CRMP-2 expression. The SP1, E2F, and GATA1/2 binding sites appeared to play some roles in regulation of CRMP-2 expression. As expected, the CRMP-2 protein accumulated in extended neurites of TGW cells treated with GDNF. However, neuritogenesis of TGW cells was mostly dependent on Src family kinase activity and not ERK activity, indicating that the increased expression of CRMP-2 alone was not sufficient for neuritogenesis.
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PMID:Induction of CRMP-2 by GDNF and analysis of the CRMP-2 promoter region. 1520 9

Previously, it was shown that the recruitment of RET into lipid rafts by glial cell line-derived neurotrophic factor (GDNF)/GFRalpha1 is crucial for efficient signal transduction. Here, we show that the mouse GFRalpha4 is a functional, N-glycosylated, glycosylphosphatidylinositol (GPI)-anchored protein, which mediates persephin (PSPN)-induced phosphorylation of RET, but has an almost undetectable capacity to recruit RET into the 0.1% Triton X-100 insoluble membrane fraction. In spite of this, PSPN/mGFRalpha4 promotes neurite outgrowth in PC6-3 cells and survival of cerebellar granule neurons. As we show that also human PSPN/GFRalpha4 is unable to recruit RET into lipid rafts, we propose that the mammalian GFRalpha4 in this respect differs from GFRalpha1.
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PMID:PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. 1522 46

Pancreatic carcinoma cells exhibit a pronounced tendency to invade along and into intra- and extrapancreatic nerves, even at early stages of the disease. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) has been shown to promote pancreatic cancer cell invasion. Here, we demonstrate that pancreatic carcinoma cell lines, such as PANC-1, expressed the RET and GDNF family receptor alpha receptor components for GDNF and that primary pancreatic tumor samples, derived from carcinomas with regional lymph node metastasis, exhibited marked expression of the mRNA encoding the RET51 isoform. Moreover, GDNF was an efficacious and potent chemoattractant for pancreatic carcinoma cells as examined in in vitro and in vivo model systems. Treatment of PANC-1 cells with GDNF resulted in activation of the monomeric GTPases N-Ras, Rac1, and RhoA, in activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and in activation of the phosphatidylinositol 3-kinase/Akt pathway. Both inhibition of the Ras-Raf-MEK (mitogen-activated protein/ERK kinase)-ERK cascade by either stable expression of dominant-negative H-Ras(N17) or addition of the MEK1 inhibitor PD98059 as well as inhibition of the phosphatidylinositol 3-kinase pathway by LY294002 prevented GDNF-induced migration and invasion of PANC-1 cells. These results demonstrate that pancreatic tumor cell migration and possibly perineural invasion in response to GDNF is critically controlled by activation of the Ras-Raf-MEK-ERK and the phosphatidylinositol 3-kinase pathway.
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PMID:Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. 1528 35

Grb2-associated binder-1 (Gab1) is a docking protein closely related to insulin receptor substrates. We previously reported that tyrosine 1062 in RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF) represents a binding site for the Shc-Grb2-Gab1 complex, and that the p85 subunit of phosphatidylinositol 3-kinase (PI3K) and SHP2 tyrosine phosphatase is associated with Gab1 in GDNF-treated cells. In the present study, we further analyzed the physiological roles of Gab1 downstream of RET, using Gab1 mutants that lack the binding sites for PI3K (Gab1 PI3K-m) or SHP-2 (Gab1 SHP2-m). Expression of Gab1 PI3K-m in SK-N-MC human primitive neuroectodermal tumor cells expressing wild-type RET markedly impaired Akt phosphorylation, Rac1 activation, and lamellipodia formation that were induced by GDNF whereas expression of Gab1 SHP2-m partially impaired Erk activation. Furthermore, expression of Gab1 PI3K-m, but not Gab1 SHP2-m, in TT human medullary thyroid carcinoma cells expressing RET with a multiple endocrine neoplasia 2A mutation enhanced cytochrome c release, and apoptosis induced by etoposide, suggesting that PI3K is involved in survival of TT cells via a mitochondrial pathway. These findings demonstrated that coupling of Gab1 to PI3K is important for biological responses in RET-expressing cells.
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PMID:Biochemical and biological responses induced by coupling of Gab1 to phosphatidylinositol 3-kinase in RET-expressing cells. 1535 43

The glial cell line-derived neurotrophic factor (GDNF) family coreceptor alpha1 (GFRalpha1) is a critical component of the RET receptor kinase signal-transducing complex. The activity of this multicomponent receptor is stimulated by the glial cell line-derived neurotrophic factor (GDNF) and is involved in neuronal cells survival and kidney development. GFRalpha1 pre-mRNA is alternatively spliced and produces two isoforms: GFRalpha1a, which includes the exon 5; and GFRalpha1b, which excludes it. Here we show that the Gfralpha1a isoform is predominantly expressed in neuronal tissues and in PC12 cells differentiated toward a neuronal phenotype. GFRalpha1 splicing is also regulated during kidney development, GFRalpha1a is the minor isoform before birth and then rapidly becomes the major form after birth. We established cell lines expressing either GFRalpha1 isoforms and demonstrated that the GFRalpha1b isoform binds GDNF more efficiently than GFRalpha1a. Consistently, GFRalpha1b promotes a stronger RET phosphorylation than GFRalpha1a. These results indicate that specific inclusion of the GFRalpha1 exon 5 in neuronal tissues or during kidney development may alter the binding properties of GDNF to GFRalpha1, and thus could constitute an additional regulatory mechanism of the RET signaling pathway.
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PMID:Expression of GFRalpha1 receptor splicing variants with different biochemical properties is modulated during kidney development. 1538 Dec 58

Glial cell line-derived neurotrophic factor (GDNF) family ligands are target-derived trophic factors for several neuronal subpopulations. They promote survival and neurite outgrowth through binding to specific members of the GDNF family receptor alpha (GFR alpha) and subsequent activation of the RET tyrosine kinase receptor. Using compartmentalized cultures of sympathetic neurons, we have studied the mechanism of GDNF retrograde signaling. Our results demonstrate the presence of GDNF receptors RET and GFR alpha 1 in the two cellular compartments, cell bodies and distal axons. Addition of GDNF to either compartment initiated local signaling, including activation of RET and its downstream effectors AKT and ERK1/2. Addition of GDNF to distal axons induced a retrograde signal leading to neuronal survival and neurite outgrowth. Retrograde signaling was associated with retrograde transport of radiolabeled GDNF and GFR alpha 1, as well as activation of RET and AKT, but not of ERK1/2, in cell bodies. No anterograde signal propagation or transport was observed. Our results suggest a general mechanism for retrograde signaling initiated at distal axons through tyrosine kinase receptors.
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PMID:Retrograde propagation of GDNF-mediated signals in sympathetic neurons. 1548 69


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