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)

In Drosophila, over 50 genes have been identified in which loss-of-function mutations lead to excess cell proliferation in the embryo, in the central nervous system, imaginal discs or hematopoietic organs of the larva, or in the adult gonads. Twenty-two of these genes have been cloned and characterized at the molecular level, and nine of them show clear homology to mammalian genes. Most of these mammalian genes had not been previously implicated in cell proliferation control. Overgrowth in some of the mutants involves conversion to a cell type that, in normal development, shows more cell proliferation than the original cell type. Thus the neurogenic mutants, including Notch, show conversion of epidermal cells to neuroblasts, leading to the 'neurogenic' phenotype of excess nervous tissue. The ovarian tumor mutants show conversion of the female germ line to a cell type resembling the male germ line, which undergoes more proliferation than the female germ line. Mutations of the fat locus cause hyperplastic overgrowth of imaginal discs, in which the epithelial structure is largely intact. The predicted fat protein product is a giant relative of cadherins, supporting indications from human cancer that cadherins play an important role in tumor suppression. Mutations in the lethal(2)giant larvae and lethal(1)discs large genes cause neoplastic overgrowth of imaginal discs as well as the larval brain. The dlg gene encodes a membrane-associated guanylate kinase homolog that is localized at septate junctions between epithelial cells. This protein is a member of a family of homologs that also includes two proteins found at mammalian tight junctions (ZO-1 and ZO-2) and a protein found at mammalian synaptic junctions (PSD-95/SAP90). Genes in which mutations cause blood cell overproduction include aberrant immune response-8, which encodes the RpS6 ribosomal protein and hopscotch, which encodes a putative non-receptor protein tyrosine kinase. The gene products identified by ovarian tumor mutants do not show clear amino acid sequence homology to known proteins. Drosophila provides an opportunity to rapidly identify and characterize tumor suppressor genes, many of which have mammalian homologs that might also be involved in cell proliferation control and tumor suppression.
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PMID:Drosophila in cancer research: the first fifty tumor suppressor genes. 788 89

The ERBB receptors have a crucial role in morphogenesis and oncogenesis. We have identified a new PDZ protein we named ERBIN (ERBB2 interacting protein) that acts as an adaptor for the receptor ERBB2/HER2 in epithelia. ERBIN contains 16 leucine-rich repeats (LRRs) in its amino terminus and a PDZ (PSD-95/DLG/ZO-1) domain at its carboxy terminus, and belongs to a new PDZ protein family. The PDZ domain directly and specifically interacts with ERBB2/HER2. ERBIN and ERBB2/HER2 colocalize to the lateral membrane of human intestinal epithelial cells. The ERBIN-binding site in ERBB2/HER2 has a critical role in restricting this receptor to the basolateral membrane of epithelial cells, as mutation of the ERBIN-binding site leads to the mislocalization of the receptor in these cells. We suggest that ERBIN acts in the localization and signalling of ERBB2/HER2 in epithelia.
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PMID:ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor. 1087 17

Identification of protein complexes associated with the ERBB2/HER2 receptor may help unravel the mechanisms of its activation and regulation in normal and pathological situations. Interactions between ERBB2/HER2 and Src homology 2 or phosphotyrosine binding domain signaling proteins have been extensively studied. We have identified ERBIN and PICK1 as new binding partners for ERBB2/HER2 that associate with its carboxyl-terminal sequence through a PDZ (PSD-95/DLG/ZO-1) domain. This peptide sequence acts as a dominant retention or targeting basolateral signal for receptors in epithelial cells. ERBIN belongs to the newly described LAP (LRR and PDZ) protein family, whose function is crucial in non vertebrates for epithelial homeostasis. Whereas ERBIN appears to locate ERBB2/HER2 to the basolateral epithelium, PICK1 is thought to be involved in the clustering of receptors. We show here that ERBIN and PICK1 bind to ERBB2/HER2 with different mechanisms, and we propose that these interactions are regulated in cells. Since ERBIN and PICK1 tend to oligomerize, further complexity of protein networks may participate in ERBB2/HER2 functions and specificity.
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PMID:The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins. 1127 3

Inhibitors of both phosphatidylinositol-3-kinase (PI3-kinase) and MAPK/ERK (mitogen-activate protein kinase/extracellular signal-related kinase) activation inhibit NMDA receptor-dependent long-term potentiation (LTP). PI3-kinase inhibitors also block activation of ERK by NMDA receptor stimulation, suggesting that PI3-kinase inhibitors block LTP because PI3-kinase is an essential upstream regulator of ERK activation. To examine this hypothesis, we investigated the effects of PI3-kinase inhibitors on ERK activation and LTP induction in the CA1 region of mouse hippocampal slices. Consistent with the notion that ERK activation by NMDA receptor stimulation is PI3-kinase dependent, the PI3-kinase inhibitor wortmannin partially inhibited ERK2 activation induced by bath application of NMDA and strongly suppressed ERK2 activation by high-frequency synaptic stimulation. PI3-kinase and MEK (MAP kinase kinase) inhibitors had very different effects on LTP, however. Both types of inhibitors suppressed LTP induced by theta-frequency trains of synaptic stimulation, but only PI3-kinase inhibitors suppressed the induction of LTP by high-frequency stimulation or low-frequency stimulation paired with postsynaptic depolarization. Concentrations of PI3-kinase inhibitors that inhibited LTP when present during high-frequency stimulation had no effect on potentiated synapses when applied after high-frequency stimulation, suggesting that PI3-kinase is specifically involved in the induction of LTP. Finally, we found that LTP induced by theta-frequency stimulation was MEK inhibitor insensitive but still PI3-kinase dependent in hippocampal slices from PSD-95 (postsynaptic density-95) mutant mice. Together, our results indicate that the role of PI3-kinase in LTP is not limited to its role as an upstream regulator of MAPK signaling but also includes signaling through ERK-independent pathways that regulate LTP induction.
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PMID:Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms. 1273 39

Cupidin (Homer 2/vesl-2) is a post-synaptic adaptor protein that associates with glutamate receptor complexes and the actin cytoskeleton. We analyzed the developmental and activity-dependent localization of Cupidin in mouse cerebellar granule cells. Cupidin is predominantly localized to granule cell post-synapses connecting with mossy fiber terminals in developing post-natal cerebellum, but is diminished in adult cerebellum. In cultured granule cells 7 days in vitro, Cupidin was present as synaptic and extra-synaptic punctate clusters that largely co-localized with the actin-cytoskeletal binding partners F-actin and drebrin, as well as a post-synaptic scaffold protein PSD-95. Upon stimulation with glutamate, Cupidin clusters were rapidly dissociated without protein degradation, and by short-term but not sustained stimulation they were recovered after post-incubation without glutamate. The glutamate-induced declustering of Cupidin preceded that of F-actin and drebrin, was elicited by NMDA receptor-mediated Ca2+ influx, and was followed by a downstream pathway including MAPK/ERK and protein tyrosine kinase. Specific isoforms with post-translational modification were reduced depending on Ca2+-dependent protein phosphatase activity. In cultured hippocampal neurons, Homer family members Homer 1, Cupidin/Homer 2 and Homer 3 showed similar glutamate-induced declustering. We suggest that Cupidin acts as a mobile adaptor protein that changes the distribution states, clustered versus declustered, in response to synaptic activity.
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PMID:Glutamate-induced declustering of post-synaptic adaptor protein Cupidin (Homer 2/vesl-2) in cultured cerebellar granule cells. 1451 Nov 14

SAPK3 (stress-activated protein kinase-3, also known as p38gamma) is a member of the mitogen-activated protein kinase family; it phosphorylates substrates in response to cellular stress, and has been shown to bind through its C-terminal sequence to the PDZ domain of alpha1-syntrophin. In the present study, we show that SAP90 [(synapse-associated protein 90; also known as PSD-95 (postsynaptic density-95)] is a novel physiological substrate for both SAPK3/p38gamma and the ERK (extracellular-signal-regulated protein kinase). SAPK3/p38gamma binds preferentially to the third PDZ domain of SAP90 and phosphorylates residues Thr287 and Ser290 in vitro, and Ser290 in cells in response to cellular stresses. Phosphorylation of SAP90 is dependent on the binding of SAPK3/p38gamma to the PDZ domain of SAP90. It is not blocked by SB 203580, which inhibits SAPK2a/p38alpha and SAPK2b/p38beta but not SAPK3/p38gamma, or by the ERK pathway inhibitor PD 184352. However, phosphorylation is abolished when cells are treated with a cell-permeant Tat fusion peptide that disrupts the interaction of SAPK3/p38gamma with SAP90. ERK2 also phosphorylates SAP90 at Thr287 and Ser290 in vitro, but this does not require PDZ-dependent binding. SAP90 also becomes phosphorylated in response to mitogens, and this phosphorylation is prevented by pretreatment of the cells with PD 184352, but not with SB 203580. In neurons, SAP90 and SAPK3/p38gamma co-localize and they are co-immunoprecipitated from brain synaptic junctional preparations. These results demonstrate that SAP90 is a novel binding partner for SAPK3/p38gamma, a first physiological substrate described for SAPK3/p38gamma and a novel substrate for ERK1/ERK2, and that phosphorylation of SAP90 may play a role in regulating protein-protein interactions at the synapse in response to adverse stress- or mitogen-related stimuli.
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PMID:Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2. 1474 Oct 46

The specification and organization of glutamatergic synaptic transmission require the coordinated interaction among glutamate receptors and their synaptic adaptor proteins closely assembled in the postsynaptic density (PSD). Here we investigated the interaction between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5) in the integral regulation of extracellular signal-regulated protein kinase (ERK) and gene expression in cultured rat striatal neurons. We found that coapplication of NMDA and the mGluR5 agonist (S)-3,5-dihydroxyphenylglycine synergistically increased ERK phosphorylation. Interestingly, the synergistic increase in ERK phosphorylation was dependent on the cross talk between NMDA receptor-associated synaptic adaptor protein PSD-95 and the mGluR5-linked adaptor protein Homer1b/c but not on the conventional Ca2+ signaling derived from NMDA receptors (Ca2+ influx) and mGluR5 (intracellular Ca2+ release). This was demonstrated by the findings that the synergistic phosphorylation of ERK induced by coactivation of NMDA receptors and mGluR5 was blocked by either a Tat peptide that disrupts NMDA receptor/PSD-95 binding or small interfering RNAs that selectively reduce cellular levels of Homer1b/c. Furthermore, ERK activated through this PSD-95/Homer1b/c-dependent and Ca2+-independent pathway was able to phosphorylate the two key transcription factors Elk-1 and cAMP response element-binding protein, which further leads to facilitation of c-Fos expression. Together, we have identified a novel Ca2+-independent signaling pathway to ERK by the synergistic interaction of NMDA receptors and mGluR5 via their adaptor proteins in the PSD of neurons, which underlies a synapse-to-nucleus communication important for the transcriptional regulation.
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PMID:A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. 1557 35

In our previous studies we showed that apoE treatment of neurons activated ERK 1/2 signaling, and activation was blocked by treatment with inhibitors of the low density lipoprotein receptor family, the N-methyl-d-aspartate (NMDA) receptor antagonist MK 801, and calcium channel blockers. We hypothesized an interaction between the low density lipoprotein receptor family members and the NMDA receptor. In the present study, we confirmed through co-immunoprecipitation experiments an interaction between the apoE receptor, ApoEr2, and NMDAR1 through their extracellular domains. We also found that the PDZ1 domain of PSD95, a postsynaptic scaffolding protein, interacted with the C terminus of ApoEr2 via an alternatively spliced, intracellular exon. This interaction between ApoEr2 and PSD95 in neurons was modulated by NMDA receptor activation and an ApoEr2 ligand. We also found that the PDZ2 domain of PSD95 interacted with the NR2A and NR2B subunits of NMDA receptors. Full-length PSD95 increased cell surface levels of ApoEr2 and its cleavage, resulting in increases in secreted ApoEr2 and C-terminal fragments of ApoEr2. These studies suggest that ApoEr2 can form a multiprotein complex with NMDA receptor subunits and PSD95.
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PMID:Apolipoprotein E receptor 2 interactions with the N-methyl-D-aspartate receptor. 1633 82

The receptor protein tyrosine kinase Met and its ligand, hepatocyte growth factor, regulate cellular morphology, intercellular adhesion, and interactions among junctional proteins in numerous cell types. However, they have not been extensively studied in the central nervous system. We report that Met is clustered at excitatory synapses and that treatment of neurons with hepatocyte growth factor can enhance expression and clustering of synaptic proteins. We demonstrate that Met is present in clusters that strongly colocalize with the NR2B subunit of the N-methyl-D-aspartate receptor, PSD-95 and synapsin at excitatory synapses of hippocampal neurons in vitro. We also show that Met is clustered at the postsynaptic density of excitatory synapses in the CA1 region of the hippocampus with the use of immuno-electron microscopy. Hepatocyte growth factor also forms clusters that partially colocalize with PSD-95. Treatment of cultured neurons with exogenous hepatocyte growth factor increased expression of the NR2B subunit of the N-methyl-D-aspartate receptor, calcium/calmodulin-dependent protein kinase II, and the GluR1 subunit of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor. The size and number of clusters of these proteins were also increased at sites along dendrites in response to hepatocyte growth factor. These results suggest a novel role for Met and hepatocyte growth factor in regulating synapses.
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PMID:The receptor tyrosine kinase Met and its ligand hepatocyte growth factor are clustered at excitatory synapses and can enhance clustering of synaptic proteins. 1686 28

In a previous study we have shown that SGS742, a cognitive enhancer acting by GABA(B) receptor antagonism improved spatial learning in OF1 mice. The aim of the study was therefore to screen representatives of several signaling cascades known to be involved in memory formation at the protein level. NaCl-, SGS742- treatment and yoked controls for NaCl and SGS742 were studied. Six hours following testing OF1 mice in the Morris water maze, hippocampal signaling proteins calmodulin kinase II (CaMKII) (phosphorylated (P) and non-phosphorylated (NP) form), CREB (P, NP), ERK (P, NP), BDNF, Egr-1, Trk-B and neuro-cytoskeleton elements drebrin and PSD-95 were determined by immunoblotting. Protein patterns were comparable between the control and SGS742 treated group revealing that these proteins may not be involved in the mechanisms underlying cognitive enhancement by SGS742 and this should be taken into account for interpretation and design of previous and future related neurochemical studies.
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PMID:The cognitive enhancer SGS742 does not involve major known signaling cascades in OF1 mice. 1832 94


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