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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a preceding paper, we reported a novel actin filament (F-actin)-binding protein, named neurabin, which was specifically expressed in neural tissue and implicated in neurite formation. We purified from rat brain another F-actin-binding protein, which had a domain organization similar to that of neurabin but was ubiquitously expressed, and named it neurabin-II. The original neurabin, renamed neurabin-I, had 1095 amino acids and a calculated Mr of 122,729, whereas neurabin-II had 817 amino acids and a calculated Mr of 89, 642. Both neurabin-I and -II had one F-actin-binding domain at the N-terminal region, one PDZ domain at the middle region, a domain known to interact with transmembrane proteins, and domains predicted to form coiled-coil structures at the C-terminal region. Both neurabin-I and -II bound along the sides of F-actin and showed F-actin-cross-linking activity. The subcellular distribution analysis indicated that neurabin-II was enriched at the postsynaptic density fraction in rat brain and the adherens junction fraction in rat liver. Immunofluorescence microscopic analysis revealed that neurabin-II was highly concentrated at the synapse in primary cultured rat hippocampal neurons and at the cadherin-based cell-cell adhesion sites in Madin-Darby canine kidney cells. Neurabin-II turned out to be the same as a recently reported protein phosphatase 1-binding protein named spinophilin. These results suggest that neurabin-II/spinophilin plays an important role in linking the actin cytoskeleton to the plasma membrane.
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PMID:Neurabin-II/spinophilin. An actin filament-binding protein with one pdz domain localized at cadherin-based cell-cell adhesion sites. 945 70

We have recently isolated a rat homologue of the Caenorrhabditis elegans lin-10 product. Although rat lin-10 is expressed in the cytosol and membrane fractions of various tissues, it is distributed only in the membrane fraction in brain where it is enriched in the synaptic plasma membrane and postsynaptic density fractions. We have isolated here a rat lin-10-interacting protein from rat brain and identified it to be neurabin-II/spinophilin, which has recently been isolated as a protein interacting with protein phosphatase I and F-actin. Neurabin-II/spinophilin is ubiquitously expressed but enriched in brain, especially in the synaptic plasma membrane and postsynaptic density fractions. We discuss the physiological significance of the interaction of rat lin-10 with neurabin-II/spinophilin.
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PMID:Interaction of rat lin-10 with brain-enriched F-actin-binding protein, neurabin-II/spinophilin. 951 10

Tyrosine phosphoproteins of size 115-120 kDa were purified from membranes of chicken embryo fibroblasts (CEF) infected with Rous sarcoma virus (RSV). A mouse was immunized with these proteins, and the immune serum was used to screen a CEF cDNA expression library. A highly immunoreactive clone (KS5) was identified and characterized. The cDNA of this clone is 2.3 kb in length with a short 5' UTR and a single major open reading frame (ORF) encoding a polypeptide of 719 amino acids, with a calculated molecular weight of 81.1 kDa. The encoded protein contains an amino terminal PDZ domain, followed by a predicted coiled-coil region, a PEST domain, and a carboxy-terminal SAM domain. Consensus sequence motifs for tyrosine phosphorylation are also present, as are consensus sequences for the binding of SH2 and PDZ domains. Antisera from mice immunized with bacterially expressed fragments of the KS5 protein recognized proteins of size 230, 116, and 65 kDa in CEF. In other chicken embryo tissues, a 116-kDa species was the predominant protein recognized. The 116-kDa species is tyrosine-phosphorylated in RSV-CEF. The presence of PDZ and SAM domains in the KS5 protein suggests that it may act as a molecular adaptor, promoting and relaying information in a signal transduction pathway. It is a member of a family of related proteins, all of which have a highly conserved PDZ domain adjacent to a coiled-coil region. Two other members of this family are the neuronal proteins spinophilin (Allen, P.B., Ouimet, C.C., Greengard, P., 1997. Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc. Natl. Acad. Sci. USA 94, 9956-9961) and neurabin (Nakanishi, H., Obaishi, H., Satoh, A., Wada, M., Mandai, K., Satoh, K., Nishioka, H., Matsuura, Y., Mizoguchi, A. , Takai, Y., 1997. Neurabin: A novel neural tissue-specific actin filament-binding protein involved in neurite formation. J. Cell Biol. 139, 951-961).
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PMID:An avian cDNA encoding a tyrosine-phosphorylated protein with PDZ, coiled-coil, and SAM domains. 975 12

Modulation of AMPA-type glutamate channels is important for synaptic plasticity. Here we provide physiological evidence that the activity of AMPA channels is regulated by protein phosphatase 1 (PP-1) in neostriatal neurons and identify two distinct molecular mechanisms of this regulation. One mechanism involves control of PP-1 catalytic activity by DARPP-32, a dopamine- and cAMP-regulated phosphoprotein highly enriched in neostriatum. The other involves binding of PP-1 to spinophilin, a protein that colocalizes PP-1 with AMPA receptors in postsynaptic densities. The results suggest that regulation of anchored PP-1 is important for AMPA-receptor-mediated synaptic transmission and plasticity.
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PMID:Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. 1019 74

Signaling through D2 class dopamine receptors is crucial to correct brain development and function, and dysfunction of this system is implicated in major neurological disorders such as Parkinson's disease and schizophrenia. To investigate potential novel mechanisms of D2 receptor regulation, the third cytoplasmic loop of the D2 dopamine receptor was used to screen a rat hippocampal yeast two-hybrid library. Spinophilin, a recently characterized F-actin and protein phosphatase-1-binding protein with a single PDZ domain was identified as a protein that specifically associates with this region of D2 receptors. A direct interaction between spinophilin and the D2 receptor was confirmed in vitro using recombinant fusion proteins. The portion of spinophilin responsible for interacting with the D2 third cytoplasmic loop was narrowed to a region that does not include the actin-binding domain, the PDZ domain, or the coiled-coil. This region is distinct from the site of interaction with protein phosphatase-1, and both D2 receptors and protein phosphatase-1 may bind spinophilin at the same time. The interaction is not mediated via the unique 29-amino acid insert in D2long; both D2long and D2short third cytoplasmic loops interact with spinophilin in vitro and in yeast two-hybrid assays. Expression of D2 receptors containing an extracellular hemagglutinin epitope in Madin-Darby canine kidney cells results in co-localization of receptor and endogenous spinophilin as determined by immunocytochemistry using antibodies directed against spinophilin and the HA tag. We hypothesize that spinophilin is important for establishing a signaling complex for dopaminergic neurotransmission through D2 receptors by linking receptors to downstream signaling molecules and the actin cytoskeleton.
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PMID:Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. 1039 35

We previously characterized PP1bp134 and PP1bp175, two neuronal proteins that bind the protein phosphatase 1 catalytic subunit (PP1). Here we purify from rat brain actin-cytoskeletal extracts PP1(A) holoenzymes selectively enriched in PP1gamma(1) over PP1beta isoforms and also containing PP1bp134 and PP1bp175. PP1bp134 and PP1bp175 were identified as the synapse-localized F-actin-binding proteins spinophilin (Allen, P. B., Ouimet, C. C., and Greengard, P. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 9956-9561; Satoh, A., Nakanishi, H., Obaishi, H., Wada, M., Takahashi, K., Satoh, K., Hirao, K., Nishioka, H., Hata, Y., Mizoguchi, A., and Takai, Y. (1998) J. Biol. Chem. 273, 3470-3475) and neurabin (Nakanishi, H., Obaishi, H., Satoh, A., Wada, M., Mandai, K., Satoh, K., Nishioka, H. , Matsuura, Y., Mizoguchi, A., and Takai, Y. (1997) J. Cell Biol. 139, 951-961), respectively. Recombinant spinophilin and neurabin interacted with endogenous PP1 and also with each other when co-expressed in HEK293 cells. Spinophilin residues 427-470, or homologous neurabin residues 436-479, were sufficient to bind PP1 in gel overlay assays, and selectively bound PP1gamma(1) from a mixture of brain protein phosphatase catalytic subunits; additional N- and C-terminal sequences were required for potent inhibition of PP1. Immunoprecipitation of spinophilin or neurabin from crude brain extracts selectively coprecipitated PP1gamma(1) over PP1beta. Moreover, immunoprecipitation of PP1gamma(1) from brain extracts efficiently coprecipitated spinophilin and neurabin, whereas PP1beta immunoprecipitation did not. Thus, PP1(A) holoenzymes containing spinophilin and/or neurabin target specific neuronal PP1 isoforms, facilitating efficient regulation of synaptic phosphoproteins.
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PMID:Brain actin-associated protein phosphatase 1 holoenzymes containing spinophilin, neurabin, and selected catalytic subunit isoforms. 1058 69

Spinophilin, a protein that interacts with actin and protein phosphatase-1, is highly enriched in dendritic spines. Here, through the use of spinophilin knockout mice, we provide evidence that spinophilin modulates both glutamatergic synaptic transmission and dendritic morphology. The ability of protein phosphatase-1 to regulate the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors was reduced in spinophilin knockout mice. Consistent with altered glutamatergic transmission, spinophilin-deficient mice showed reduced long-term depression and exhibited resistance to kainate-induced seizures and neuronal apoptosis. In addition, deletion of the spinophilin gene caused a marked increase in spine density during development in vivo as well as altered filopodial formation in cultured neurons. In conclusion, spinophilin appears to be required for the regulation of the properties of dendritic spines.
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PMID:Spinophilin regulates the formation and function of dendritic spines. 1092 77

Regulation of protein phosphatase 1 (PP1) by protein inhibitors and targeting subunits has been previously studied through the use of recombinant protein expressed in Escherichia coli. This preparation is limited by several key differences in its properties compared with native PP1. In the present study, we have analyzed recombinant PP1 expressed in Sf9 insect cells using baculovirus. Sf9 PP1 exhibited properties identical to those of native PP1, with respect to regulation by metals, inhibitor proteins, and targeting subunits, and failure to dephosphorylate a phosphotyrosine-containing substrate or phospho-DARPP-32 (Dopamine and cAMP-regulated phosphoprotein, M(r) 32,000). Mutations at Y272 in the beta12/beta13 loop resulted in a loss of activity and reduced the sensitivity to thiophospho-DARPP-32 and inhibitor-2. Mutations of Y272 also increased the relative activity toward a phosphotyrosine-containing substrate or phospho-DARPP-32. Mutation of acidic groove residues caused no change in sensitivity to thiophospho-DARPP-32 or inhibitor-2, but one mutant (E252A:D253A:E256R) exhibited an increased K(m) for phosphorylase a. Several PP1/PP2A chimeras were prepared in which C-terminal sequences of PP2A were substituted into PP1. Replacement of residues 274-330 of PP1 with the corresponding region of PP2A resulted in a large loss of sensitivity to thiophospho-DARPP-32 and inhibitor-2, and also resulted in a loss of interaction with the targeting subunits, spinophilin and PP1 nuclear targeting subunit (PNUTS). More limited alterations in residues in beta12, beta13, and beta14 strands highlighted a key role for M290 and C291 in the interaction of PP1 with thiophospho-DARPP-32, but not inhibitor-2.
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PMID:Protein phosphatase 1 regulation by inhibitors and targeting subunits. 1124 35

The INK4a gene, one of the most often disrupted loci in human cancer, encodes two unrelated proteins, p16(INK4a) and p14(ARF) (ARF) both capable of inducing cell cycle arrest. Although it has been clearly demonstrated that ARF inhibits cell cycle via p53 stabilization, very little is known about the involvement of ARF in other cell cycle regulatory pathways, as well as on the mechanisms responsible for activating ARF following oncoproliferative stimuli. In search of factors that might associate with ARF to control its activity or its specificity, we performed a yeast two-hybrid screen. We report here that the human homologue of spinophilin/neurabin II, a regulatory subunit of protein phosphatase 1 catalytic subunit specifically interacts with ARF, both in yeast and in mammalian cells. We also show that ectopic expression of spinophilin/neurabin II inhibits the formation of G418-resistant colonies when transfected into human and mouse cell lines, regardless of p53 and ARF status. Moreover, spinophilin/ARF coexpression in Saos-2 cells, where ARF ectopic expression is ineffective, somehow results in a synergic effect. These data demonstrate a role for spinophilin in cell growth and suggest that ARF and spinophilin could act in partially overlapping pathways.
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PMID:The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein. 1127 17

Plasticity in dendritic spines may underlie learning and memory. Spinophilin, a protein enriched in dendritic spines, has the properties of a scaffolding protein and is believed to regulate actin cytoskeletal dynamics affecting dendritic spine morphology. It also binds protein phosphatase-1 (PP-1), an enzyme that regulates dendritic spine physiology. In this study, we tested the role of spinophilin in conditioned taste aversion learning (CTA) using transgenic spinophilin knockout mice. CTA is a form of associative learning in which an animal rejects a food that has been paired previously with a toxic effect (e.g., a sucrose solution paired with a malaise-inducing injection of lithium chloride). Acquisition and extinction of CTA was tested in spinophilin knockout and wild-type mice using taste solutions (sucrose or sodium chloride) or flavors (Kool-Aid) paired with moderate or high doses of LiCl (0.15 M, 20 or 40 mL/kg). When sucrose or NaCl solutions were paired with a moderate dose of LiCl, spinophilin knockout mice were unable to learn a CTA. At the higher dose, knockout mice acquired a CTA but extinguished more rapidly than wild-type mice. A more salient flavor stimulus (taste plus odor) revealed similar CTA learning at both doses of LiCl in both knockouts and wild types. Sensory processing in the knockouts appeared normal because knockout mice and wild-type mice expressed identical unconditioned taste preferences in two-bottle tests, and identical lying-on-belly responses to acute LiCl. We conclude that spinophilin is a candidate molecule required for normal CTA learning.
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PMID:Impaired conditioned taste aversion learning in spinophilin knockout mice. 1158 74


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