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

---

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

The RET receptor tyrosine kinase plays a critical role in the development of the enteric nervous system (ENS) and the kidney. Upon glial-cell-line-derived neurotrophic factor (GDNF) stimulation, RET can activate a variety of intracellular signals, including the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/AKT, and RAC1/JUN NH(2)-terminal kinase (JNK) pathways. We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner. To determine the importance of cAMP-dependent modification of the RET signal in vivo, we generated mutant mice in which serine residue 697, a putative protein kinase A (PKA) phosphorylation site, was replaced with alanine (designated S697A mice). Homozygous S697A mutant mice lacked the ENS in the distal colon, resulting from a migration defect of enteric neural crest cells (ENCCs). In vitro organ culture showed an impaired chemoattractant response of the mutant ENCCs to GDNF. JNK activation by GDNF but not ERK, AKT and SRC activation was markedly reduced in neurons derived from the mutant mice. The JNK inhibitor SP600125 and the PKA inhibitor KT5720 suppressed migration of the ENCCs in cultured guts from wild-type mice to comparable degrees. Thus, these findings indicated that cAMP-dependent modification of RET function regulates the JNK signaling responsible for proper migration of the ENCCs in the developing gut.
...
PMID:Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. 1705 Jun 26

Glial cell-line derived neurotrophic factor (GDNF)-mediated RET tyrosine kinase signaling is implicated in the survival of several PNS and CNS neuronal populations that are important in the pathogenesis of several disorders including Parkinson's disease and drug addiction. However, it has been difficult to study these processes and the physiological importance of this pathway in adult mice because of the neonatal lethality of Gdnf and Ret null mice. We report successful creation of RET conditional reporter mice to investigate postnatal physiologic roles of RET and monitor the fate of RET-expressing cell types. To delete RET specifically in dopaminergic neurons and determine the physiologic requirement of RET in the maintenance of substantia nigra compacta (SNC) and ventral tegmental area (VTA), we bred the RET conditional mice with mice that specifically express Cre from the dopamine transporter (Dat) locus. A detailed morphometric and biochemical analysis including dopaminergic neuron number and size in SNC and VTA, and fiber density in the striatum and nucleus accumbens, and dopamine levels indicate that RET is not required for providing global trophic support to midbrain dopaminergic neurons in adult mice. Furthermore, RET deficiency in these neurons does not cause major sensorimotor abnormalities. Hence our results support the idea that RET signaling is not critical for the normal physiology of the SNC and VTA in adult mice.
...
PMID:RET is dispensable for maintenance of midbrain dopaminergic neurons in adult mice. 1706 62

The t(2;5) chromosomal translocation occurs in anaplastic large-cell lymphoma arising from activated T lymphocytes. This genomic rearrangement generates the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) oncoprotein that is a chimeric protein consisting of parts of the nuclear protein NPM and ALK receptor protein-tyrosine kinase. We used yeast two-hybrid screening to identify an adaptor protein Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target (SNT)-2 as a new partner that interacted with the cytoplasmic domain of ALK. Immunoprecipitation assay revealed that SNT-1 and SNT-2 interacted with NPM-ALK and kinase-negative NPM-ALK mutant. Y156, Y567 and a 19-amino-acid sequence (aa 631-649) of NPM-ALK were essential for this interaction. The interaction through Y156 and Y567 was dependent on phosphorylation of these tyrosines, whereas the interaction through the 19-amino-acid sequence was independent of phosphorylation. NPM-ALK mutant protein mutated at these three binding sites showed significantly reduced transforming activity. This transformation-defective NPM-ALK mutant still interacted with signal transducing proteins such as phospholipase C-gamma and phosphatidylinositol 3-kinase, which were previously reported to be relevant to NPM-ALK-dependent tumorigenesis. These observations indicate that the three SNT-binding sites of NPM-ALK are important for its transforming activity. This raises a possibility that SNT family proteins play significant roles in cellular transformation triggered by NPM-ALK, which though remains to be verified.
...
PMID:Identification of multiple SNT-binding sites on NPM-ALK oncoprotein and their involvement in cell transformation. 1708 10

Basic fibroblast growth factor (FGF-2) is a physiological relevant neurotrophic factor in the nigrostriatal system and hence a promising candidate for the establishment of alternative therapeutic strategies in Parkinson's disease. FGF-2 and its high-affinity receptors (FGFR) display an expression in the developing, postnatal, and adult substantia nigra (SN) and in the striatum. Exogenous application promoted survival, neurite outgrowth and protection from neurotoxin-induced death of dopaminergic (DA) neurons both in vitro and in vivo. In animal models of Parkinson's disease, co-transplantation of fetal DA cells with FGF-2 expressing cells increased survival and functional integration of the grafted DA neurons resulting in improved behavioral performance. Analyzing the physiological function of the endogenous FGF-2 system during development and after neurotoxin-induced lesion revealed for the DA neurons of the SNpc a dependence on FGFR3 signaling during development. In addition, in the absence of FGF-2 an increased number of DA neurons was found, whereas enhanced levels of FGF-2 resulted in a reduced DA cell density. Following neurotoxin-induced lesion of DA neurons, FGF-2-deleted mice displayed a higher extent of DA neuron death whereas in FGF-2 overexpressing mice more DA neurons were protected. According to the data, FGF-2 seems to promote DA neuron survival via FGFR3 during development, whereas absence of this ligand could be compensated by other members of the FGF family. In contrast, in the adult organism, FGF-2 cannot be compensated by other factors under lesion conditions suggesting a central role for this molecule in the nigrostriatal system.
...
PMID:The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system. 1722 67

Vascular endothelial growth factor (VEGF-A) plays multiple roles in kidney development: stimulates cell proliferation, survival, tubulogenesis, and branching morphogenesis. However, the mechanism that mediates VEGF-A induced ureteric bud branching is unclear. Glial-derived neurotrophic factor (GDNF) signaling through tyrosine kinase c-RET is the major regulator of ureteric bud branching. Here we examined whether VEGF-A regulates RET signaling. We determined that ureteric bud-derived cells express the main VEGF-A signaling receptor, VEGFR2 and RET, by RT-PCR, immunoblotting, and immunocytochemistry. We show that the VEGF-A isoform VEGF(165) induces RET-tyr(1062) phosphorylation in addition to VEGFR2 autophosphorylation, that VEGF(165) and GDNF have additive effects on RET-tyr(1062) phosphorylation, and that VEGFR2 and RET co-immunoprecipitate. Functionally, VEGF(165) induces ureteric bud cell proliferation and branching morphogenesis. Similarly, in embryonic kidney explants VEGF(165) induces RET-tyr(1062) phosphorylation and upregulates GDNF. These findings provide evidence for a novel cooperative interaction between VEGFR2 and RET that mediates VEGF-A functions in ureteric bud cells.
...
PMID:Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways. 1749 Jun 19

Rat pups reared apart from their siblings, mother, and nest environment in the 'pup-in-a-cup' regime show many alterations in behavior reminiscent of the Institutional Inattention/Overactivity Syndrome that characterizes children whose first few months are spent in institutions. In this report, we compare mother-reared (MR) and artificially reared (AR) male rats in concentrations and distributions of brain proteins that are involved in normal brain development. When assessed during the juvenile period and in adulthood, AR animals showed elevations in Neu-N (a neuronal marker) and in S-100 (an astrocyte marker) but reductions in synaptophysin (synapse protein), N-CAM (cell-adhesion molecule), GAP-43 (axon elongation protein), and BDNF (brain derived neurotrophic factor) in comparison to MR controls in many brain sites involved in attention, impulsivity, activity, and social behavior. Daily 'licking-like' stimulation provided to AR animals (AR-MAX) throughout early development that reverses many of the behavioral deficits, also reverses many of the isolation effects on brain proteins. Study 2 showed that elevations in the number of neurons in combination with decreases in functionality are associated with a reduction in neuronal pruning and apoptosis during the very early post-partum period in AR animals and their reversal through daily 'licking-like' stimulation.
...
PMID:Maternal isolation alters the expression of neural proteins during development: 'Stroking' stimulation reverses these effects. 1755 25

Glial cell derived neurotrophic factor (GDNF)-dependent receptor tyrosine kinase RET activity is required for proper development of the nervous system and genitourinary tract. Loss-of-function mutations in RET are associated with enteric nervous system abnormalities (Hirschsprung disease) and renal deficits (Potter's syndrome), whereas activating mutations lead to hereditary cancer syndromes (multiple endocrine neoplasia type 2A and type 2B). RET activation is crucial for the proper regulation of a variety of cellular processes including cell migration, proliferation and neurite outgrowth. By analyzing a series of RET mutants we found that Y1062 was critical for stimulating GDNF-mediated proliferation as well as proliferation stimulated by GDNF-independent oncogenic forms of RET. Studies using small interfering RNA driven by lentivirus to knock-down expression of particular adaptor proteins that interact with RET phospho-Y1062, demonstrated that only Src-homology 2 and growth factor receptor binding protein 2 were necessary for RET-mediated proliferation by wild type and oncogenic forms of RET. Interestingly, we discovered that Y1062 was also required for GDNF-stimulated neurite outgrowth. However, small interfering RNAs to either Src-homology 2 or growth factor receptor binding protein 2 or a panel of other adaptor proteins known to interact with RET Y1062 were incapable of blocking GDNF-stimulated neurite formation, indicating that differential use of intracellular adaptors is responsible for regulating alternative RET-stimulated cellular events such as proliferation versus a differentiation response like neurite outgrowth.
...
PMID:Deciphering adaptor specificity in GFL-dependent RET-mediated proliferation and neurite outgrowth. 1766 53

In Parkinson's and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (-)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-kappaB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.
...
PMID:Neuroprotection by propargylamines in Parkinson's disease: intracellular mechanism underlying the anti-apoptotic function and search for clinical markers. 1798 85

It was previously observed that IL-1beta interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support [Tong L., Balazs R., Soiampornkul R., Thangnipon W., Cotman C.W., 2007. Interleukin-1beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol. Aging]. Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general. The influence of IL-1beta on NT-3 signaling was therefore studied under conditions when NT-3 primarily activated the TrkC receptor. The cytokine reduced NT-3-induced activation of MAPK/ERK and Akt, but did not interfere with Trk receptor autophosphorylation. IL-1beta reduced tyrosine phosphorylation of the docking proteins, IRS-1 and Shc, which convey receptor activation to the downstream protein kinase cascades. These are the steps that are also inhibited by IL-1beta in BDNF-induced signal transduction. The functional consequences of the effect of IL-1beta on NT-3 signaling were severe, as NT-3 protection of the trophic support-deprived cortical neurons was abrogated. In view of the role in the maintenance and plasticity of neurons of ERK, Akt and CREB, which are activated by neurotrophins, elevated IL-1beta levels in the brain in Alzheimer's disease and other neurodegenerative diseases might contribute to the decline in cognitive functions before the pathological signs of the disease develop.
...
PMID:Interleukin-1beta interferes with signal transduction induced by neurotrophin-3 in cortical neurons. 1803 76

Activation of the RET (rearranged during transfection) receptor by glial cell-line-derived neurotrophic factor (GDNF) has been identified as an important differentiation and survival factor for dopaminergic neurons of the midbrain in preclinical experiments. These encouraging results have led to clinical trials of GDNF in patients with Parkinson's disease, which have resulted in conflicting findings. To investigate the potential benefit of Ret-dependent signaling on the challenged dopaminergic system, we tested the effect of tissue-selective ablation of the Ret gene on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, the most widely used animal model for Parkinson's disease. Ablation of Ret did not modify the MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and the dopaminergic innervation of the striatum at 14 days. However, Ret ablation abolished the regeneration of dopaminergic fibers and terminals, as well as the partial recovery of striatal dopamine concentrations, that was observed in control mice between days 14 and 90 after MPTP treatment. We therefore conclude that RET signaling has no influence on the survival of dopaminergic neurons in the MPTP model of Parkinson's disease but rather facilitates the regeneration of dopaminergic axon terminals.
...
PMID:RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals. 1805 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---