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)

Delta-like 4 (Dll4), a membrane-bound ligand for Notch1 and Notch4, is selectively expressed in the developing endothelium and in some tumor endothelium, and it is induced by vascular endothelial growth factor (VEGF)-A and hypoxia. Gene targeting studies have shown that Dll4 is required for normal embryonic vascular remodeling, but the mechanisms underlying Dll4 regulatory functions are currently not defined. In this study, we generated primary human endothelial cells that overexpress Dll4 protein to study Dll4 function and mechanism of action. Human umbilical vein endothelial cells retrovirally transduced with Dll4 displayed reduced proliferative and migratory responses selectively to VEGF-A. Expression of VEGF receptor-2, the principal signaling receptor for VEGF-A in endothelial cells, and coreceptor neuropilin-1 was significantly decreased in Dll4-transduced endothelial cells. Consistent with Dll4 signaling through Notch, expression of HEY2, one of the transcription factors that mediates Notch function, was significantly induced in Dll4-overexpressing endothelial cells. The gamma-secretase inhibitor L-685458 significantly reconstituted endothelial cell proliferation inhibited by immobilized extracellular Dll4 and reconstituted VEGFR2 expression in Dll4-overexpressing endothelial cells. These results identify the Notch ligand Dll4 as a selective inhibitor of VEGF-A biologic activities down-regulating 2 VEGF receptors expressed on endothelial cells and raise the possibility that Dll4 may be exploited therapeutically to modulate angiogenesis.
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PMID:Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. 1621 2

Signaling by stem cell factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a glycoprotein receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-cell lymphomas. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family kinases, phosphatidylinositol 3-kinase, phospholipase Cgamma, and Ras/mitogen-activated protein kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control alphaC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted protein-tyrosine kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoprotein of chronic myelogenous leukemia) at their ATP-binding sites.
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PMID:Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor. 1622 10

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed in specific areas of the developing central and peripheral nervous systems. We previously demonstrated that a membrane-bound and constitutively active form of the ALK protein tyrosine kinase (PTK) domain induced the neuron-like differentiation of PC12 cells through specific activation of the mitogen-activated protein kinase (MAP kinase) pathway. Its PTK domain had been originally identified in a nucleo-cytosolic and constitutively active transforming protein, NPM-ALK. Downstream targets involved in oncogenic proliferation and survival processes have been proposed to include phospholipase Cgamma (PLCgamma), phosphoinositide 3-kinase (PI 3-kinase)/AKT, STAT 3/5 and Src. We therefore postulated that activation of specific signaling pathways leading to differentiation or proliferation can be differently controlled depending on the subcellular localization of ALK PTK domain. To increase knowledge of its physiological role in the nervous system, we focused in the present study on the influence of its subcellular localization on neuronal differentiation. To achieve this goal, we characterized biological responses and transduction pathways in PC12 cells elicited by various constructs encoding membrane-bound (through transmembrane or myristyl sequences) or cytosolic ALK-derived proteins. In order to control the activation of their PTK domain, we used an inducible dimerization system. Here, we demonstrate that membrane attachment of the ALK PTK domain, in PC12 cells, is crucial for initiation of neurite outgrowth and proliferation arrest through a decrease of DNA synthesis. Furthermore, we show that this differentiation process relies on specific and sustained activation of ERK 1/2 proteins. By contrast, activation of the cytosolic form of this domain fails to induce MAP kinase activation and cell differentiation but promotes a PI 3-kinase/AKT-dependent PC12 cell proliferation. These data indicate that subcellular localization of the ALK PTK domain was a determinant for the control and specificity of downstream transduction cascades and was crucial for deciding the fate to which the neuronal cell will be committed.
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PMID:Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells. 1631 43

Neurturin (NRTN), artemin (ARTN), persephin (PSPN) and glial cell line-derived neurotrophic factor (GDNF) form a group of neurotrophic factors, also known as the GDNF family ligands (GFLs). They signal through a receptor complex composed of a high-affinity ligand binding subunit, postulated ligand specific, and a common membrane-bound tyrosine kinase RET. Recently, also NCAM has been identified as an alternative signaling receptor. GFLs have been reported to promote survival of cultured dopaminergic neurons. In addition, GDNF treatments have been shown to increase morphological differentiation of tyrosine hydroxylase immunoreactive (TH-ir) neurons. The present comparative study investigated the dose-dependent effects of GFLs on survival and morphological differentiation of TH-ir neurons in primary cultures of E14 rat ventral mesencephalon. Both NRTN and ARTN chronically administered for 5 days significantly increased survival and morphological differentiation of TH-ir cells at all doses investigated [0.1-100 ng/ml], whereas PSPN was found to be slightly less potent with effects on TH-ir cell numbers and morphology at 1.6-100 ng/ml and 6.3-100 ng/ml, respectively. In conclusion, our findings identify NRTN, ARTN and PSPN as potent neurotrophic factors that may play an important role in the structural development and plasticity of ventral mesencephalic dopaminergic neurons.
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PMID:The GDNF family members neurturin, artemin and persephin promote the morphological differentiation of cultured ventral mesencephalic dopaminergic neurons. 1632 3

Stannin (Snn) was discovered using subtractive hybridization methodology designed to find gene products related to selective organotin toxicity and apoptosis. The cDNAs for Snn were first isolated from brain tissues sensitive to trimethyltin, and were subsequently used to localize, characterize, and identify genomic DNA, and other gene products of Snn. Snn is a highly conserved, 88 amino acid protein found primarily in vertebrates. There is a minor divergence in the C-terminal sequence between amphibians and primates, but a nearly complete conservation of the first 60 residues in all vertebrates sequenced to date. Snn is a membrane-bound protein and is localized, in part, to the mitochondria and other vesicular organelles, suggesting that both localization and conservation are significant for the overall function of the protein. The structure of Snn in a micellar environment and its architecture in lipid bilayers have been determined using a combination of solution and solid-state NMR, respectively. Snn structure comprised a single transmembrane domain (residues 10-33), a 28-residue linker region from residues 34-60 that contains a conserved CXC metal binding motif and a putative 14-3-3xi binding region, and a cytoplasmic helix (residues 61-79), which is partially embedded into the membrane. Of primary interest is understanding how this highly-conserved peptide with an interesting structure and cellular localization transmits both normal and potentially toxic signals within the cell. Evidence to date suggests that organotins such as trimethyltin interact with the CXC region of Snn, which is vicinal to the putative 14-3-3 binding site. In vitro transfection analyses and microarray experiments have inferred a possible role of Snn in several key signaling systems, including activation of the p38-ERK cascade, p53-dependent pathways, and 14-3-3xi protein-mediated processes. TNFalpha can induce Snn mRNA expression in endothelial cells in a PKC-epsilon dependent manner. Studies with Snn siRNA suggest that this protein may be involved in growth regulation, since inhibition of Snn expression alone leads to reduced endothelial cells growth and induction of COP-1, a negative regulator of p53 function. A key piece of the puzzle, however, is how and why such a highly-conserved protein, localized to mitochondria, interacts with other regulatory proteins to alter growth and apoptosis. By knowing the structure, location, and possible signaling pathways involved, we propose that Snn constitutes an important sensor of mitochondrial damage, and plays a key role in the mediation of cross-talk between mitochondrial and nuclear compartments in specific cell types.
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PMID:Functional and structural properties of stannin: roles in cellular growth, selective toxicity, and mitochondrial responses to injury. 1645 79

The HER-2 receptor tyrosine kinase is an important regulator of cell proliferation and survival, and it is a clinically validated target of therapeutic intervention for HER-2 positive breast cancer patients. Its extracellular domain (ECD) is frequently cleaved by protease(s) in HER-2 overexpressing breast cancer patients, rendering the remaining membrane-bound portion (p95) a constitutively activated kinase. The presence of both serum ECD and cellular p95 protein has been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments. We have identified a series of potent, selective small molecule inhibitors of ADAM proteases, exemplified here by INCB003619, and demonstrate that these inhibitors effectively block HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. Intriguingly, when used in combination, INCB003619 dramatically enhances the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Furthermore, INCB003619, in combination with trastuzumab, augments the pro-apoptotic and antiproliferative effects of the chemotherapeutic agent paclitaxel. Consistent with these in vitro data, INCB003619 reduces serum ECD levels and enhances the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors may represent a novel therapeutic approach for treating HER-2 overexpressing breast cancer patients.
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PMID:Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab. 1662 88

Most gastrointestinal stromal tumors (GISTs) possess a gain-of-function mutation in c-KIT. Imatinib mesylate, a small-molecule inhibitor against several receptor tyrosine kinases, including KIT, platelet-derived growth factor receptor-alpha, and BCR-ABL, has therapeutic benefit for GISTs both via KIT and via unknown mechanisms. Clinical evidence suggests that a potential therapeutic benefit of imatinib might result from decreased glucose uptake as measured by positron emission tomography using 18-fluoro-2-deoxy-d-glucose. We sought to determine the mechanism of and correlation to altered metabolism and cell survival in response to imatinib. Glucose uptake, cell viability, and apoptosis in GIST cells were measured following imatinib treatment. Lentivirus constructs were used to stably express constitutively active AKT1 or AKT2 in GIST cells to study the role of AKT signaling in metabolism and cell survival. Immunoblots and immunofluorescent staining were used to determine the levels of plasma membrane-bound glucose transporter Glut4. We show that oncogenic activation of KIT maximizes glucose uptake in an AKT-dependent manner. Imatinib treatment markedly reduces glucose uptake via decreased levels of plasma membrane-bound Glut4 and induces apoptosis or growth arrest by inhibiting KIT activity. Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation. Overall, these findings contribute to a clearer understanding of the molecular mechanisms involved in the therapeutic benefit of imatinib in GIST and suggest that a drug-mediated decrease in tumor metabolism observed clinically may not entirely reflect therapeutic efficacy of treatment.
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PMID:Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. 1670 77

Degradation of activated ERBB receptors is an important mechanism for signal attenuation. However, compared with epidermal growth factor (EGF) receptor, the ERBB2/ERBB3 signaling pair is considered to be attenuation-deficient. The ERBB2/ERBB3 ligands of the neuregulin family rely on an EGF-like domain for signaling and are generated from larger membrane-bound precursors. In contrast to EGF, which is processed to yield a 6-kDa peptide ligand, mature neuregulins retain a variety of segments N-terminal to the EGF-like domain. Here we evaluate the role of the N-terminal domain of neuregulin 1 in signaling and turnover of ERBB2/ERBB3. Our data suggest that whereas the EGF-like domain of neuregulin 1 is required and sufficient for the formation of active receptor heterodimers, the presence of the N-terminal Ig-like domain is required for efficient signal attenuation. This manifests itself for both ERBB2 and ERBB3 but is more pronounced and coupled directly to degradation for ERBB3. When stimulated with only the EGF-like domain, ERBB3 shows degradation rates comparable with constitutive turnover, but stimulation with full-length neuregulin 1 resulted in receptor degradation at rates that are comparable with activated EGF receptor. Most of the enhancement in down-regulation was maintained after replacing the Ig-like domain with a thioredoxin protein of comparable size but different amino acid composition, suggesting that the physical presence but not specific properties of the Ig-like domain are needed. This sequence-independent effect of the N-terminal domain correlates with an enhanced ability of full-size neuregulin 1 to disrupt higher order oligomers of the ERBB3 extracellular domains in vitro.
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PMID:The N-terminal domains of neuregulin 1 confer signal attenuation. 1682 99

The regulation of cell function by fibroblast growth factors (FGF) occurs through a dual receptor system consisting of a receptor-tyrosine kinase, FGFR and the glycosaminoglycan heparan sulfate (HS). Mutations of some potential N-glycosylation sites in human fgfr lead to phenotypes characteristic of receptor overactivation. To establish how N-glycosylation may affect FGFR function, soluble- and membrane-bound recombinant receptors corresponding to the extracellular ligand binding domain of FGFR1-IIIc were produced in Chinese Hamster Ovary cells. Both forms of FGFR1-IIIc were observed to be heavily N-glycosylated and migrated on SDS-PAGE as a series of multiple bands between 50 and 75 kDa, whereas the deglycosylated receptors migrated at 32 kDa, corresponding to the expected molecular weight of the polypeptides. Optical biosensor and quartz crystal microbalance-dissipation binding assays show that the removal of the N-glycans from FGFR1-IIIc caused an increase in the binding of the receptor to FGF-2 and to heparin-derived oligosaccharides, a proxy for cellular HS. This effect is mediated by N-glycosylation reducing the association rate constant of the receptor for FGF-2 and heparin oligosaccharides. N-Glycans were analyzed by mass spectrometry, which demonstrates a predominance of bi- and tri-antennary core-fucosylated complex type structures carrying one, two, and/or three sialic acids. Modeling of such glycan structures on the receptor protein suggests that at least some may be strategically positioned to interfere with interactions of the receptor with FGF ligand and/or the HS co-receptor. Thus, the N-glycans of the receptor represent an additional pathway for the regulation of the activity of FGFs.
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PMID:N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding. 1682 30

Four-transmembrane-domain proteins of the tetraspanin superfamily are the organizers of specific microdomains at the membrane [TERMs (tetraspanin-enriched microdomains)] that incorporate various transmembrane receptors and modulate their activities. The structural aspects of the organization of TERM are poorly understood. In the present study, we investigated the role of gangliosides in the assembly and stability of TERM. We demonstrated that inhibition of the glycosphingolipid biosynthetic pathway with specific inhibitors of glucosylceramide synthase [NB-DGJ (N-butyldeoxygalactonojirimycin) and PPMP (D-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol.HCl)] resulted in specific weakening of the interactions involving tetraspanin CD82. Furthermore, ectopic expression of the plasma-membrane-bound sialidase Neu3 in mammary epithelial cells also affected stability of the complexes containing CD82: its association with tetraspanin CD151 was decreased, but the association with EGFR [EGF (epidermal growth factor) receptor] was enhanced. The destabilization of the CD82-containing complexes upon ganglioside depletion correlated with the re-distribution of the proteins within plasma membrane. Importantly, depletion of gangliosides affected EGF-induced signalling only in the presence of CD82. Taken together, our results provide strong evidence that gangliosides play an important role in supporting the integrity of CD82-enriched microdomains. Furthermore, these results demonstrate that the association between different tetraspanins in TERM is controlled by distinct mechanisms and identify Neu3 as a first physiological regulator of the integrity of these microdomains.
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PMID:Gangliosides play an important role in the organization of CD82-enriched microdomains. 1685 90


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