Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Smad proteins are critical intracellular signaling mediators for the transforming growth factor beta (TGFbeta) superfamily. Here, we report that Erbin (for "ErbB2/Her2-interacting protein"), which contains leucine-rich repeats and a PDZ (PSD-95/DLG/ZO-1) domain, interacts specifically with Smad3 and, to a lesser extent, with Smad2 through a novel Smad-interacting domain (SID) adjacent to its PDZ domain. Increased expression of Erbin does not affect the level of TGFbeta-induced phosphorylation of Smad2/Smad3, but it physically sequesters Smad2/Smad3 from their association with Smad4 and hence negatively modulates TGFbeta-dependent transcriptional responses and cell growth inhibition. An isoform of Erbin encoded by an alternatively spliced transcript in human tissues lacks this SID and fails to inhibit TGFbeta responses. Consistently, knockdown of the endogenous Erbin gene with short hairpin RNA enhances TGFbeta-induced antiproliferative and transcriptional responses. In addition, Erbin suppresses activin/Smad2-dependent, but not BMP/Smad1-mediated, induction of endogenous gene expression in Xenopus embryos. Therefore, these results define Erbin as a novel negative modulator of Smad2/Smad3 functions and expand the physiological role of Erbin to the regulation of TGFbeta signaling.
Mol Cell Biol 2007 Sep
PMID:Erbin inhibits transforming growth factor beta signaling through a novel Smad-interacting domain. 1759 1

Net1 is a RhoA-specific guanine nucleotide exchange factor which localizes to the nucleus at steady state. A deletion in its N terminus redistributes the protein to the cytosol, where it activates RhoA and can promote transformation. Net1 contains a PDZ-binding motif at the C terminus which is essential for its transformation properties. Here, we found that Net1 interacts through its PDZ-binding motif with tumor suppressor proteins of the Dlg family, including Dlg1/SAP97, SAP102, and PSD95. The interaction between Net1 and its PDZ partners promotes the translocation of the PDZ proteins to nuclear subdomains associated with PML bodies. Interestingly, the oncogenic mutant of Net1 is unable to shuttle the PDZ proteins to the nucleus, although these proteins still associate as clusters in the cytosol. Our results suggest that the ability of oncogenic Net1 to transform cells may be in part related to its ability to sequester tumor suppressor proteins like Dlg1 in the cytosol, thereby interfering with their normal cellular function. In agreement with this, the transformation potential of oncogenic Net1 is reduced when it is coexpressed with Dlg1 or SAP102. Together, our results suggest that the interaction between Net1 and Dlg1 may contribute to the mechanism of Net1-mediated transformation.
Mol Cell Biol 2007 Dec
PMID:The nuclear RhoA exchange factor Net1 interacts with proteins of the Dlg family, affects their localization, and influences their tumor suppressor activity. 1793 6

Dexras1, a brain-enriched member of the Ras subfamily of GTPases, as a novel physiologic nitric oxide (NO) effector, anchor neuronal nitric oxide synthase (nNOS) that increased after spinal cord injury (SCI), to specific targets to enhance NO signaling, and is strongly and rapidly induced during treatment with dexamethasone. It is unknown how the central nervous system (CNS) trauma affects the expression of Dexras1. Here we used spinal cord transection (SCT) model to detect expression of Dexras1 at mRNA and protein level in spinal cord homogenates by real-time PCR and Western blot analysis. The results showed that Dexras1 mRNA upregulated at 3 day, 5 day, and 7 day significantly (P < 0.05) that was consistent with the protein level except at 7 day. Immunofluorescence revealed that both neurons and glial cells showed Dexras1 immunoreactivivty (IR) around SCT site, but the proportion is different. Importantly, injury-induced expression of Dexras1 was co-labeled by caspase-3 (apoptotic marker) and Tau-1 (marker for pathological oligodendrocyte). Furthermore, colocalization of Dexras1, carboxy-terminal PSD95/DLG/ZO-1 (PDZ) ligand of nNOS (CAPON) and nNOS was observed in neurons and glial cells, supporting the existence of ternary complexes in this model. Thus, the results that the transient high expression of Dexras1 which localized in apoptotic neurons and pathological oligodendrocytes might provide new insight into the secondary response after SCT.
Cell Mol Neurobiol 2008 May
PMID:Spatiotemporal expression of Dexras1 after spinal cord transection in rats. 1821 71

Activity-dependent local translation in the dendrites of brain neurons plays an important role in the synapse-specific provision of proteins necessary for strengthening synaptic connections. In this study we carried out combined fluorescence in situ hybridization (FISH) and immunocytochemistry (IC) and showed that more than half of the eukaryotic elongation factor 1A (eEF1A) mRNA clusters overlapped with or were immediately adjacent to clusters of PSD-95, a postsynaptic marker, in the dendrites of cultured rat hippocampal neurons. Treatment of the neurons with KCl increased the density of the dendritic eEF1A mRNA clusters more than two-fold. FISH combined with IC revealed that the KCl treatment increased the density of eEF1A mRNA clusters that overlapped with or were immediately adjacent to PSD-95 clusters. These results indicate that KCl treatment increases both the density of eEF1A mRNA clusters and their synaptic association in dendrites of cultured neurons.
Mol Cells 2008 Jun 30
PMID:Upregulation by KCl treatment of eukaryotic translation elongation factor 1A (eEF1A) mRNA in the dendrites of cultured rat hippocampal neurons. 1844 10

The N-methyl-D-aspartate receptor (NMDAR) is a Ca(2+)-permeable glutamate receptor mediating many neuronal functions under normal and pathological conditions. Ca(2+) influx via NMDARs activates diverse intracellular targets, including Ca(2+)-dependent protease calpain. Biochemical studies suggest that NR2A and NR2B subunits of NMDARs are substrates of calpain. Our physiological data showed that calpain, activated by prolonged NMDA treatment (100 microM, 5 min) of cultured cortical neurons, irreversibly decreased the whole-cell currents mediated by extrasynaptic NMDARs. Animals exposed to transient forebrain ischemia, a condition that activates calpain, exhibited the reduced NMDAR current density and the lower full-length NR2A/B level in a calpain-dependent manner. Disruption of the association between NMDARs and the scaffolding protein postsynaptic density (PSD)-95 facilitated the calpain regulation of synaptic NMDAR responses and NR2 cleavage in cortical slices, whereas inhibition of calcineurin activity blocked the calpain effect on NMDAR currents and NR2 cleavage. Calpain-cleaved NR2B subunits were removed from the cell surface. Moreover, cell viability assays showed that calpain, by targeting NMDARs, provided a negative feedback to dampen neuronal excitability in excitotoxic conditions. These data suggest that calpain activation suppresses NMDAR function via proteolytic cleavage of NR2 subunits in vitro and in vivo, and the susceptibility of NMDARs to calpain cleavage is controlled by PSD-95 and calcineurin.
Mol Pharmacol 2008 Aug
PMID:Postsynaptic density-95 (PSD-95) and calcineurin control the sensitivity of N-methyl-D-aspartate receptors to calpain cleavage in cortical neurons. 1844 9

For the zonula adherens (ZA) to be established by linear arrangement of adherens junctions (AJs) in epithelial sheet cells, critical for the epithelial cell sheet formation and intercellular barrier function, myosin-2 is supposedly integrated into the ZA with the result of overlapping localization of E-cadherin/actin/myosin-2. Here, we immunofluorescently showed that myosin-2 failed to be integrated into the ZA in cultured epithelial-type ZO1(ko)/2(kd) Eph4 cells lacking ZO-1 and -2 (zonula occludens-1 and -2) by knockout and knockdown, respectively. Instead, a linearized but fragmented arrangement of AJs was formed in the way that it was positive for E-cadherin/actin, but negative for myosin-2 (designated prezonula-AJ). Transfection of full-length ZO-1 or ZO-2, or ZO-1 lacking its PDZ (PSD-95/discs large/zonula occludens-1)-1/2 domains (but not one lacking PDZ-1/2/3) into ZO1(ko)/2(kd) Eph4 cells restored the junctional integration of myosin-2 with prezonula-AJ to establish the ZA. Transfection of dominant-active RhoA or Rho-kinase (ROCK), as well as administration of lysophosphatidic acid or Y27632, which activates RhoA or inhibits ROCK, respectively, suggested that RhoA regulated the junctional integration of myosin-2 into ZA in a manner such that ROCK played a necessary but not-sufficient role. Fluorescence resonance energy transfer analyses revealed that spatiotemporal Rho-activation occurred in a ZO-1/2-dependent way to establish ZA from primordial forms in epithelial cells.
Mol Biol Cell 2008 Sep
PMID:ZO-1- and ZO-2-dependent integration of myosin-2 to epithelial zonula adherens. 1859 33

Excitability of individual neurons dictates the overall excitation in specific brain circuits. This process is thought to be regulated by molecules that regulate synapse number, morphology and strength. Neuronal excitation is also influenced by the amounts of neurotransmitter receptors and signaling molecules retained at particular synaptic sites. Recent studies revealed a key role for PSD-95, a scaffolding molecule enriched at glutamatergic synapses, in modulation of clustering of several neurotransmitter receptors, adhesion molecules, ion channels, cytoskeletal elements and signaling molecules at postsynaptic sites. In this review we will highlight mechanisms that control targeting of PSD-95 at the synapse, and discuss how this molecule influences the retention and clustering of diverse synaptic proteins to regulate synaptic structure and strength. We will also discuss how PSD-95 may maintain a balance between excitation and inhibition in the brain and how alterations in this balance may contribute to neuropsychiatric disorders.
Front Mol Neurosci 2008
PMID:Excitation Control: Balancing PSD-95 Function at the Synapse. 1894 37

The mood-stabilizing effects of lithium are well documented, although its mechanism of action remains unknown. Increases in gray matter volume detected in patients with bipolar disorder who were treated with lithium suggest that changes in the number of synapses might underlie its therapeutic effects. We investigated the effects of lithium on the number of synaptic connections between hippocampal neurons in culture. Confocal imaging of neurons expressing postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP) enabled visualization of synaptic sites. PSD95-GFP fluorescent puncta represented functional synapses, and lithium (4 h, 5 mM) increased their number by 150 +/- 12%. The increase was time- and concentration-dependent (EC(50) = 1.0 +/- 0.6 mM). Lithium induced a parallel increase in the presynaptic marker synaptophysin-GFP. Valproic acid, another mood stabilizer, also increased the number of fluorescent puncta at a clinically relevant concentration. Inhibition of postsynaptic glutamate receptors or presynaptic inhibition of neurotransmitter release significantly reduced lithium-induced synapse formation, indicating that glutamatergic synaptic transmission was required. Pretreatment with exogenous myo-inositol inhibited synapse formation, demonstrating that depletion of inositol was necessary to increase synaptic connections. In contrast, inhibition of glycogen synthase kinase 3beta did not mimic lithium-induced synapse formation. Pharmacological and lipid reconstitution experiments showed that new synapses formed as a result of depletion of phosphatidylinositol-4-phosphate rather than a build-up of polyphosphoinositides or changes in the activity of phospholipase C, protein kinase C, or phosphatidylinositol-3-kinase. Increased synaptic connections may underlie the mood-stabilizing effects of lithium in patients with bipolar disorder and could contribute to the convulsions produced by excessive doses of this drug.
Mol Pharmacol 2009 May
PMID:Lithium increases synapse formation between hippocampal neurons by depleting phosphoinositides. 1918 38

Sema4C is a transmembrane protein that belongs to axon guidance molecules of semaphorin family. Previous reports have shown that Sema4C could interact with postsynaptic protein PSD95, etc, but the expression and the role of Sema4C in neurogenesis remains unknown. In this study, whole-mount in situ hybridization result showed that Sema4C was expressed abundantly in the areas of lateral ventricle, the striatum, the wall of midbrain, and the pons/midbrain junction of E11.5 embryos brain. Neural stem/progenitor cells (NSPs) obtained from E13.5 embryonic rat midbrain are also positive for Sema4C immunoreactivity. Sema4C expression was dramatically downregulated during induction of NSP differentiation. In order to confirm the involvement of Sema4C in neurogenesis, we used the rat global cerebral ischemia model to make adult neurogenesis in vivo. The robust proliferative NSPs were monitored by labeling with bromodeoxyuridine (BrdU) within the subventricular zone and dentate gyrus that continues for at least 2 weeks. Immunohistochemistry and Western blot analysis showed that Sema4C expression was dramatically upregulated during neurogenesis after cerebral ischemia-perfusion injury. Double immunostaining and stereologic counting analysis indicated that a high proportion of BrdU-positive proliferative cells were Nestin-positive NSPs, and also, Sema4C was highly expressed in these proliferative populations at specific stages after ischemic injury. These observations provide the evidence to support a putative role of Sema4C during neurogenesis both in vivo and in vitro.
J Mol Neurosci 2009 Sep
PMID:Sema4C expression in neural stem/progenitor cells and in adult neurogenesis induced by cerebral ischemia. 1918 44

Guanine deaminase (GDA; guanase) is a ubiquitous enzyme that catalyzes the first step of purine metabolism by hydrolytic deamination of guanine, resulting in the production of xanthine. This hydrolase subfamily member plays an essential role in maintaining homeostasis of cellular triphosphate nucleotides for energy, signal transduction pathways, and nitrogen sources. In mammals, GDA protein levels can play a role in neuronal development by regulating dendritic arborization. We previously demonstrated that the most abundant alternative splice form of GDA in mammals, termed cypin (cytosolic PSD-95 interactor), interacts with postsynaptic density proteins, regulates microtubule polymerization, and increases dendrite number. Since purine metabolism and dendrite development were previously thought to be independent cellular processes, this multifunctional protein serves as a new target for the treatment of cognitive disorders characterized by aberrant neuronal morphology and purine metabolism. Although the enzymatic activity of GDA has been conserved during evolution from prokaryotes to higher eukaryotes, a detailed evolutionary assessment of the principal domains in GDA proteins has not yet been put forward. In this study, we perform a complete evolutionary analysis of the full-length sequences and the principal domains in guanine deaminases. Furthermore, we reconstruct the molecular phylogeny of guanine deaminases with neighbor-joining, maximum-likelihood, and UPGMA methods of phylogenetic inference. This study can act as a model whereby a universal housekeeping enzyme may be adapted to act also as a key regulator of a developmental process.
J Mol Evol 2009 Mar
PMID:Phylogenetic analysis and molecular evolution of guanine deaminases: from guanine to dendrites. 1922 82


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