G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein)
G00000554 (Mus musculus)

Databases (7)

ENSG00000169862 (Ensembl human gene)
1501 (Entrez Gene)
975 (G2Cdb plasticity & disease)
CTNND2 (GeneCards)
604275 (OMIM)
Marker Symbol
HGNC:2516 (HGNC)
Protein Sequence
Q9UQB3 (UniProt)

Synonyms (2)

  • GT24

Literature (31)

Pubmed - other

  • Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.

    Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, de Kovel C, Holmes GK, Howdle PD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA and Wijmenga C

    Genetics Department, University Medical Centre, University of Groningen, Groningen, The Netherlands.

    Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts.

    Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls).

    Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression.

    Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

    Funded by: British Heart Foundation: G0000934; Medical Research Council: G0000934; Wellcome Trust: 068545/Z/02, GR068094MA

    Gut 2009;58;8;1078-83

  • Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.

    Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Maccarrone G, Dias-Neto E and Turck CW

    Laboratório de Neurociências, Instituto de Psiquiatria, Universidade de São Paulo, Rua. Dr. Ovidio Pires de Campos, no 785, Consolação, São Paulo, SP 05403-010, Brazil.

    Schizophrenia is a complex disease, likely to be caused by a combination of serial alterations in a number of genes and environmental factors. The dorsolateral prefrontal cortex (Brodmann's Area 46) is involved in schizophrenia and executes high-level functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts and attitudes, correct social behavior and personality expression. Global proteomic analysis of post-mortem dorsolateral prefrontal cortex samples from schizophrenia patients and non-schizophrenic individuals was performed using stable isotope labeling and shotgun proteomics. The analysis resulted in the identification of 1,261 proteins, 84 of which showed statistically significant differential expression, reinforcing previous data supporting the involvement of the immune system, calcium homeostasis, cytoskeleton assembly, and energy metabolism in schizophrenia. In addition a number of new potential markers were found that may contribute to the understanding of the pathogenesis of this complex disease.

    European archives of psychiatry and clinical neuroscience 2009;259;3;151-63

  • Increased nucleotide polymorphic changes in the 5'-untranslated region of delta-catenin (CTNND2) gene in prostate cancer.

    Wang T, Chen YH, Hong H, Zeng Y, Zhang J, Lu JP, Jeansonne B and Lu Q

    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

    Cancer pathogenesis involves multiple genetic and epigenetic alterations, which result in oncogenic changes in gene expression. delta-Catenin (CTNND2) is overexpressed in cancer, although the mechanisms of its upregulation are highly variable. Here we report that in prostate cancer, the methylation of CpG islands in the delta-catenin promoter was not a primary regulatory event. There was also no delta-catenin gene amplification. However, using the single-strand conformation polymorphism analysis, we observed the increased nucleotide changes in the 5'-untranslated region of delta-catenin gene in human prostate cancer. At least one such change (-9 G>A) is a true somatic point mutation associated with a high Gleason's score, poorly differentiated prostatic adenocarcinoma. Laser capture microdissection coupled with PCR analyses detected the mutation only in cancerous but not in the adjacent benign prostatic tissues. Using chimeric genes encoding the luciferase reporter, we found that this mutation, but not a random mutation or a mutation that disrupts an upstream open reading frame, resulted in a remarkably higher expression and enzyme activity. This mutation did not affect transcriptional efficiency, suggesting that it promotes delta-catenin translation. This is the first report of delta-catenin gene mutation in cancer and supports the notion that multiple mechanisms contribute to its increased expression in carcinogenesis.

    Funded by: NCI NIH HHS: CA111891, R01 CA111891, R01 CA111891-02, R01 CA111891-03

    Oncogene 2009;28;4;555-64

  • Recurrent CNVs disrupt three candidate genes in schizophrenia patients.

    Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, Strengman E, Genetic Risk and Outcome in Psychosis (GROUP) Consortium, Sabatti C, Geurts van Kessel A, Brunner HG, Ophoff RA and Veltman JA

    Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

    Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.

    Funded by: PHS HHS: R01 MG078075

    American journal of human genetics 2008;83;4;504-10

  • A genome-wide scan maps a novel high myopia locus to 5p15.

    Lam CY, Tam PO, Fan DS, Fan BJ, Wang DY, Lee CW, Pang CP and Lam DS

    Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.

    Purpose: This study was conducted to investigate the genetic component of three Chinese pedigrees originating from Hong Kong with autosomal dominant high myopia.

    Methods: A whole-genome scan was performed by using microsatellite markers spanning the whole genome with an average spacing of 10 cM. Regions containing markers that yielded LOD scores >1.0 were further analyzed by fine mapping with additional microsatellite markers. Fine-scale mapping of the linkage region was performed by genotyping a set of gene-based SNP markers on a cohort of 94 high myopia cases and 94 control subjects.

    Results: Two-point LOD scores >1 were observed at markers D5S630, D5S416, D7S510, D11S908, and D17S944. Additional microsatellite markers flanking D5S630 revealed a maximum two-point LOD score of 4.81 at D5S2505 at theta = 0.00. Haplotype analysis narrowed the linkage region to 5p15.33-p15.2 with a 17.45-cM interval. The coding sequences of five genes located within this region, IRX2, IRX1, POLS, CCT5, and CTNND2, were screened. No segregation of polymorphism with high myopia was found. Genotyping of 41 SNPs within this region in a Chinese cohort of 94 high myopia cases and 94 control subjects showed that the allele and genotype distributions of one SNP, rs370010, was different between cases and controls (genotype P = 0.01176, allele P = 0.00271 and trend P = 0.00375), but such association did not remain significant after false discovery rate (FDR) correction. This SNP is located within a hypothetical gene LOC442129.

    Conclusions: A novel autosomal dominant high myopia locus was mapped on chromosome 5p15.33-p15.2 with an interval of 17.45 cM.

    Investigative ophthalmology & visual science 2008;49;9;3768-78

  • Identification of E2F1 as a positive transcriptional regulator for delta-catenin.

    Kim K, Oh M, Ki H, Wang T, Bareiss S, Fini ME, Li D and Lu Q

    Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, 600 Moye Street, Greenville, NC 27834, USA.

    delta-Catenin is upregulated in human carcinomas. However, little is known about the potential transcriptional factors that regulate delta-catenin expression in cancer. Using a human delta-catenin reporter system, we have screened several nuclear signaling modulators to test whether they can affect delta-catenin transcription. Among beta-catenin/LEF-1, Notch1, and E2F1, E2F1 dramatically increased delta-catenin-luciferase activities while beta-catenin/LEF-1 induced only a marginal increase. Rb suppressed the upregulation of delta-catenin-luciferase activities induced by E2F1 but did not interact with delta-catenin. RT-PCR and Western blot analyses in 4 different prostate cancer cell lines revealed that regulation of delta-catenin expression is controlled mainly at the transcriptional level. Interestingly, the effects of E2F1 on delta-catenin expression were observed only in human cancer cells expressing abundant endogenous delta-catenin. These studies identify E2F1 as a positive transcriptional regulator for delta-catenin, but further suggest the presence of strong negative regulator(s) for delta-catenin in prostate cancer cells with minimal endogenous delta-catenin expression.

    Funded by: NCI NIH HHS: CA111891, R01 CA111891, R01 CA111891-03, R01 CA111891-04

    Biochemical and biophysical research communications 2008;369;2;414-20

  • Synaptic anchorage of AMPA receptors by cadherins through neural plakophilin-related arm protein AMPA receptor-binding protein complexes.

    Silverman JB, Restituito S, Lu W, Lee-Edwards L, Khatri L and Ziff EB

    Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.

    Cadherins function in the adhesion of presynaptic and postsynaptic membranes at excitatory synapses. Here we show that the cadherin-associated protein neural plakophilin-related arm protein (NPRAP; also called delta-catenin) binds via a postsynaptic density-95 (PSD-95)/discs large/zona occludens-1 (PDZ) interaction to AMPA receptor (AMPAR)-binding protein (ABP) and the related glutamate receptor (GluR)-interacting protein (GRIP), two multi-PDZ proteins that bind the GluR2 and GluR3 AMPAR subunits. The resulting cadherin-NPRAP-ABP/GRIP complexes serve as anchorages for AMPARs. Exogenous NPRAP that was bound to cadherins at adherens junctions of Madin-Darby canine kidney cells recruited ABP from the cytosol to form cadherin-NPRAP-ABP complexes, dependent on NPRAP interaction with the ABP PDZ domain 2. The cadherin-NPRAP-ABP complexes also bound GluR2. In cultured hippocampal neurons, dominant-negative mutants of NPRAP designed to disrupt tethering of ABP to NPRAP-cadherin complexes reduced surface levels of endogenous GluR2, indicating that interaction with cadherin-NPRAP-ABP complexes stabilized GluR2 at the neuronal plasma membrane. Cadherins, NPRAP, GRIP, and GluR2 copurified in the fractionation of synaptosomes and the postsynaptic density, two fractions enriched in synaptic proteins. Furthermore, synaptosomes contain NPRAP-GRIP complexes, and NPRAP localizes with the postsynaptic marker PSD-95 and with AMPARs and GRIP at spines of hippocampal neurons. Thus, tethering is likely to take place at synaptic or perisynaptic sites. NPRAP also binds PSD-95, which is a scaffold for NMDA receptors, for AMPARs in complexes with auxiliary subunits, the TARPs (transmembrane AMPA receptor regulator proteins), and for adhesion molecules. Thus, the interaction of scaffolding proteins with cadherin-NPRAP complexes may anchor diverse signaling and adhesion molecules at cadherins.

    Funded by: NCRR NIH HHS: S10 RR017970; NIA NIH HHS: AG13620, R01 AG013620, R37 AG013620; NIGMS NIH HHS: T32 GM007308, T32 GM07308

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;32;8505-16

  • Increased expression of delta-catenin/neural plakophilin-related armadillo protein is associated with the down-regulation and redistribution of E-cadherin and p120ctn in human prostate cancer.

    Lu Q, Dobbs LJ, Gregory CW, Lanford GW, Revelo MP, Shappell S and Chen YH

    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27858, USA. luq@mail.ecu.edu

    delta-Catenin, or neural plakophilin-related armadillo protein, is a unique armadillo domain-containing protein in that it is neural-specific and primarily expressed in the brain. However, our recent analysis of the human genome revealed a consistent association of delta-catenin messenger RNA sequences with malignant cells, although the significance of these findings was unclear. In this study, we report that a number of delta-catenin epitopes were expressed in human prostate cancer cells. Western blot and tissue microarray revealed a close association between increased delta-catenin expression and human primary prostatic adenocarcinomas. The analyses of 90 human prostate cancer and 90 benign prostate tissue samples demonstrated that an estimated 85% of prostatic adenocarcinomas showed enhanced delta-catenin immunoreactivity. delta-Catenin expression increased with prognostically significant increased Gleason scores. By analyzing the same tumor cell clusters using consecutive sections, we showed that an increased delta-catenin immunoreactivity was accompanied by the down-regulation and redistribution of E-cadherin and p120ctn, major cell junction proteins whose inactivation is frequently associated with cancer progression. Furthermore, overexpression of delta-catenin in tumorigenic CWR-R1 cells that are derived from human prostate cancer xenograft resulted in reduced immunoreactivity for E-cadherin and p120ctn at the cell-cell junction. This is the first study comparing overexpression of delta-catenin with the E-cadherin/catenin system in cancer and shows that delta-catenin may be intimately involved in regulating E-cadherin/p120ctn cell-cell adhesion in prostate cancer progression.

    Human pathology 2005;36;10;1037-48

  • Phosphoproteomic analysis of the developing mouse brain.

    Ballif BA, Villén J, Beausoleil SA, Schwartz D and Gygi SP

    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

    Proper development of the mammalian brain requires the precise integration of numerous temporally and spatially regulated stimuli. Many of these signals transduce their cues via the reversible phosphorylation of downstream effector molecules. Neuronal stimuli acting in concert have the potential of generating enormous arrays of regulatory phosphoproteins. Toward the global profiling of phosphoproteins in the developing brain, we report here the use of a mass spectrometry-based methodology permitting the first proteomic-scale phosphorylation site analysis of primary animal tissue, identifying over 500 protein phosphorylation sites in the developing mouse brain.

    Funded by: NHGRI NIH HHS: HG00041

    Molecular & cellular proteomics : MCP 2004;3;11;1093-101

  • The DNA sequence and comparative analysis of human chromosome 5.

    Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM and Rubin EM

    Stanford Human Genome Center, Department of Genetics, Stanford University School of Medicine, 975 California Ave, Palo Alto, California 94304, USA. jeremy@shgc.stanford.edu

    Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.

    Nature 2004;431;7006;268-74

  • Delta-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) interacts with and activates sphingosine kinase 1.

    Fujita T, Okada T, Hayashi S, Jahangeer S, Miwa N and Nakamura S

    Division of Biochemistry, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

    Sphingosine kinase (SPHK) is a key enzyme catalysing the formation of sphingosine 1-phosphate (SPP), a lipid messenger that is implicated in the regulation of a wide variety of important cellular events acting through intracellular, as well as extracellular, mechanisms. However, the molecular mechanism of intracellular actions of SPP remains unclear. Here, we have identified delta-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) as a potential binding partner for SPHK1 by yeast two-hybrid screening. From co-immunoprecipitation analyses, the C-terminal portion of delta-catenin/NPRAP containing the seventh to tenth armadillo repeats was found to be required for interaction with SPHK1. Endogenous delta-catenin/NPRAP was co-localized with endogenous SPHK1 and transfected delta-catenin/NPRAP was co-localized with transfected SPHK1 in dissociated rat hippocampal neurons. MDCK (Madin-Darby canine kidney) cells stably expressing delta-catenin/NPRAP contained elevated levels of intracellular SPP. In a purified system delta-catenin/NPRAP stimulated SPHK1 in a dose-dependent manner. Furthermore, delta-catenin/NPRAP-induced increased cell motility in MDCK cells was completely inhibited by dimethylsphingosine, a specific inhibitor of SPHK1. These results strongly suggest that at least some of delta-catenin/NPRAP functions, including increased cell motility, are mediated by an SPHK-SPP signalling pathway.

    The Biochemical journal 2004;382;Pt 2;717-23

  • Dual regulation of neuronal morphogenesis by a delta-catenin-cortactin complex and Rho.

    Martinez MC, Ochiishi T, Majewski M and Kosik KS

    Dept. of Neurology, Brigham and Women's Hospital and Harvard Medical School, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

    Delta-catenin is a neuronal protein that contains 10 Armadillo motifs and binds to the juxtamembrane segment of classical cadherins. We report that delta-catenin interacts with cortactin in a tyrosine phosphorylation-dependent manner. This interaction occurs within a region of the delta-catenin sequence that is also essential for the neurite elongation effects. Src family kinases can phosphorylate delta-catenin and bind to delta-catenin through its polyproline tract. Under conditions when tyrosine phosphorylation is reduced, delta-catenin binds to cortactin and cells extend unbranched primary processes. Conversely, increasing tyrosine phosphorylation disrupts the delta-catenin-cortactin complex. When RhoA is inhibited, delta-catenin enhances the effects of Rho inhibition on branching. We conclude that delta-catenin contributes to setting a balance between neurite elongation and branching in the elaboration of a complex dendritic tree.

    The Journal of cell biology 2003;162;1;99-111

  • The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF.

    Laura RP, Witt AS, Held HA, Gerstner R, Deshayes K, Koehler MF, Kosik KS, Sidhu SS and Lasky LA

    Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.

    Erbin is a recently described member of the LAP (leucine-rich repeat and PDZ domain) protein family. We used a C-terminally displayed phage peptide library to identify optimal ligands for the Erbin PDZ domain. Phage-selected peptides were type 1 PDZ ligands that bound with high affinity and specificity to the Erbin PDZ domain in vitro. These peptides most closely resembled the C-terminal PDZ domain-binding motifs of three p120-related catenins: delta-catenin, ARVCF, and p0071 (DSWV-COOH). Analysis of the interactions of the Erbin PDZ domain with synthetic peptides matching the C termini of ARVCF or delta-catenin also demonstrated specific high affinity binding. We characterized the interactions between the Erbin PDZ domain and both ARVCF and delta-catenin in vitro and in vivo. The Erbin PDZ domain co-localized and coprecipitated with ARVCF or delta-catenin complexed with beta-catenin and E/N-cadherin. Mutagenesis and peptide competition experiments showed that the association of Erbin with the cadherin-catenin complex was mediated by the interaction of its PDZ domain with the C-terminal PDZ domain-binding motifs (DSWV-COOH) of ARVCF and delta-catenin. Finally, we showed that endogenous delta-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that delta-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex. They also demonstrate that C-terminal phage-display technology can be used to predict physiologically relevant ligands for PDZ domains.

    The Journal of biological chemistry 2002;277;15;12906-14

  • Brain armadillo protein delta-catenin interacts with Abl tyrosine kinase and modulates cellular morphogenesis in response to growth factors.

    Lu Q, Mukhopadhyay NK, Griffin JD, Paredes M, Medina M and Kosik KS

    Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA. luq@mail.ecu.edu

    delta-Catenin associates with adhesive junctions and facilitates cellular morphogenesis (Lu et al., 1999). Here we show that delta-catenin colocalizes with actin filaments and Abl tyrosine kinase in the growth cones of cultured hippocampal neurons. PC12 cells induced to express delta-catenin show accelerated neurite extension upon nerve growth factor (NGF) stimulation. STI571, an Abl family kinase inhibitor, further accentuates these stimulatory effects. delta-Catenin is a potent substrate for Abl in vitro using an immunocomplex assay and most of the Abl-induced tyrosine phosphorylation within cells is present in the N-terminus of delta-catenin. When delta-catenin-expressing epithelial cells are induced to scatter in response to hepatocyte growth factor (HGF), STI571 leads to the rapid redistribution of delta-catenin and changes in cellular morphology. We suggest that delta-catenin is a possible Abl substrate and acts downstream of Abl to orchestrate actin-based cellular morphogenesis.

    Funded by: NIA NIH HHS: AG06601

    Journal of neuroscience research 2002;67;5;618-24

  • Densin-180 interacts with delta-catenin/neural plakophilin-related armadillo repeat protein at synapses.

    Izawa I, Nishizawa M, Ohtakara K and Inagaki M

    Division of Biochemistry, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Aichi 464-8681, Japan.

    Densin-180, a protein purified from the postsynaptic density fraction of the rat forebrain, is the founding member of a newly described family of proteins termed the LAP (leucine-rich repeats and PSD-95/Dlg-A/ZO-1 (PDZ) domains) family that plays essential roles in establishment of cell polarity. To identify Densin-180-binding proteins, we screened a yeast two-hybrid library using the carboxyl-terminal fragment of Densin-180 containing PDZ domain as bait, and we isolated delta-catenin/neural plakophilin-related armadillo repeat protein (NPRAP) as a Densin-180-interacting protein. delta-catenin/NPRAP, a member of the armadillo repeat family, is a nervous system-specific adherens junction protein originally discovered as an interactor with presenilin-1, a protein involved in Alzheimer's disease. Densin-180 PDZ domain binds the COOH terminus of delta-catenin/NPRAP containing the PDZ domain-binding sequence. Endogenous Densin-180 was co-immunoprecipitated with delta-catenin/NPRAP and N-cadherin. Although Densin-180 was reported to be a transmembrane protein, Densin-180 was not accessible to surface biotinylation in dissociated hippocampal neurons; hence Densin-180 may be a cytosolic protein. Densin-180 co-localized with delta-catenin/NPRAP at synapses in delta-catenin/NPRAP and may be involved in organization of the synaptic cell-cell junction through interaction with the delta-catenin/NPRAP-N-cadherin complex.

    The Journal of biological chemistry 2002;277;7;5345-50

  • DNA cloning using in vitro site-specific recombination.

    Hartley JL, Temple GF and Brasch MA

    Life Technologies, Inc., Rockville, Maryland 20850, USA. jhartley@lifetech.com

    As a result of numerous genome sequencing projects, large numbers of candidate open reading frames are being identified, many of which have no known function. Analysis of these genes typically involves the transfer of DNA segments into a variety of vector backgrounds for protein expression and functional analysis. We describe a method called recombinational cloning that uses in vitro site-specific recombination to accomplish the directional cloning of PCR products and the subsequent automatic subcloning of the DNA segment into new vector backbones at high efficiency. Numerous DNA segments can be transferred in parallel into many different vector backgrounds, providing an approach to high-throughput, in-depth functional analysis of genes and rapid optimization of protein expression. The resulting subclones maintain orientation and reading frame register, allowing amino- and carboxy-terminal translation fusions to be generated. In this paper, we outline the concepts of this approach and provide several examples that highlight some of its potential.

    Genome research 2000;10;11;1788-95

  • PAPIN. A novel multiple PSD-95/Dlg-A/ZO-1 protein interacting with neural plakophilin-related armadillo repeat protein/delta-catenin and p0071.

    Deguchi M, Iizuka T, Hata Y, Nishimura W, Hirao K, Yao I, Kawabe H and Takai Y

    Takai Biotimer Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd., Kobe 651-2241, Japan.

    A neural plakophilin-related armadillo repeat protein (NPRAP)/delta-catenin interacts with one of Alzheimer disease-related gene products, presenilin 1. We have previously reported the interaction of NPRAP/delta-catenin with synaptic scaffolding molecule, which is involved in the assembly of synaptic components. NPRAP/delta-catenin also interacts with E-cadherin and beta-catenin and is implicated in the organization of cell-cell junctions. p0071, a ubiquitous isoform of NPRAP/delta-catenin, is localized at desmosomes in HeLa and A431 cells and at adherens junctions in Madin-Darby bovine kidney cells. We have identified here a novel protein interacting with NPRAP/delta-catenin and p0071 and named this protein plakophilin-related armadillo repeat protein-interacting PSD-95/Dlg-A/ZO-1 (PDZ) protein (PAPIN). PAPIN has six PDZ domains and binds to NPRAP/delta-catenin and p0071 via the second PDZ domain. PAPIN and p0071 are ubiquitously expressed in various tissues and are localized at cell-cell junctions in normal rat kidney cells and bronchial epithelial cells. PAPIN may be a scaffolding protein connecting components of epithelial junctions with p0071.

    The Journal of biological chemistry 2000;275;38;29875-80

  • Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome.

    Medina M, Marinescu RC, Overhauser J and Kosik KS

    Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

    Delta-catenin is an adherens junction protein involved in cell motility and expressed early in neuronal development. It was discovered as an interactor with presenilin-1. The genomic structure of the human delta-catenin gene (Human Gene Nomenclature Committee-approved symbol CTNND2) was determined and mapped to 5p15.2. A deletion of this chromosomal region has been associated with the cri-du-chat syndrome (CDCS), a segmental aneusomy syndrome of 5p that is associated with an unusual high-pitched cry at birth, facial dysmorphology, poor growth, and severe mental retardation. delta-catenin maps to a specific region in 5p15.2 that has been implicated in the mental retardation phenotype. The breakpoints in patients with 5p terminal deletions were characterized with respect to the severity of mental retardation and the physical location of the delta-catenin gene. A strong correlation was found between the hemizygous loss of delta-catenin and severe mental retardation. These findings and the properties of delta-catenin as a neuronal-specific protein, expressed early in development and involved in cell motility, support its role in the mental retardation of CDCS when present in only one copy.

    Genomics 2000;63;2;157-64

  • The arm-repeat protein NPRAP (neurojungin) is a constituent of the plaques of the outer limiting zone in the retina, defining a novel type of adhering junction.

    Paffenholz R, Kuhn C, Grund C, Stehr S and Franke WW

    Division of Cell Biology, German Cancer Research Center, Heidelberg, Germany.

    In the retina, special plaque-bearing adhering junctions are aligned to form a planar system (the "outer limiting zone," OLZ) of heterotypic connections between the photoreceptor cells and the surrounding glial cells ("Müller cells"), together with homotypic junctions. In the plaques of these junctions, which contain N-cadherin-and possibly also related cadherins-we have identified, by immunolocalization techniques, a recently discovered neural tissue-specific protein, neurojungin, a member of the plakoglobin/armadillo protein family. In these plaques we have also detected other adherens plaque proteins, such as alpha- and beta-catenin, protein p120, and vinculin, as well as proteins known as constituents of tight junction plaques, such as symplekin and protein ZO-1, and the desmosomal plaque protein plakophilin 2. This unusual combination of proteins and the demonstrated absence of plakoglobin define the OLZ junctions as a new and distinct category of adhering junction, which probably has special architectural functions.

    Experimental cell research 1999;250;2;452-64

  • Dentatorubral-pallidoluysian atrophy protein interacts through a proline-rich region near polyglutamine with the SH3 domain of an insulin receptor tyrosine kinase substrate.

    Okamura-Oho Y, Miyashita T, Ohmi K and Yamada M

    Department of Genetics, National Children's Memorial Medical Research Center, Taishido, Setagaya, Tokyo, Japan.

    Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neuro degrees enerative disorder associated with CAG/glutamine repeat expansion. While the DRPLA gene is ubiquitously expressed, neuron death occurs in specific anatomical areas of the brain. This predicts that the DRPLA protein interacts with other proteins and that these interactions may play a role in pathogenesis. Here, we describe a protein that binds to the DRPLA product. One of the clones isolated with a yeast two-hybrid system was identified as a human homolog of the insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53). The gene produced two mRNA forms by differential splicing and encoded 552 and 521 amino acids, respectively. The longer form was mainly expressed in the brain and the shorter one in other tissues. The products were phosphorylated upon stimulation of cultured cells with insulin or insulin-like growth factor 1. Binding of the DRPLA protein to IRSp53 was ascertained by co-immunoprecipitation with antibodies and also by co-localization in perinuclear oval dots in cells expressing engineered constructs. A proline-rich region near the polyglutamine tract of the DRPLA protein and the SH3 domain of IRSp53 were involved in the binding. An extended polyglutamine tract significantly reduced binding ability in yeast cells, but not in in vitro binding assays. The identification of IRSp53 and other proteins detected by the yeast hybrid system predicts that DRPLA functions in a signal transduction pathway coupled with insulin/IGF-1.

    Human molecular genetics 1999;8;6;947-57

  • Interaction of S-SCAM with neural plakophilin-related Armadillo-repeat protein/delta-catenin.

    Ide N, Hata Y, Deguchi M, Hirao K, Yao I and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd., Kobe, 651-2241, Japan.

    Synaptic scaffolding molecule (S-SCAM) is a multiple PDZ domain-containing protein, which interacts with neuroligin, a cell adhesion molecule, and the NMDA receptor. In this study, we searched for S-SCAM-interacting proteins and obtained a neuralplakophilin-related armadillo-repeat protein (NPRAP)/delta-catenin. NPRAP/delta-catenin bound to the last PDZ domain of S-SCAM via its carboxyl-terminus in three different cell-free assay systems, was coimmunoprecipitated with S-SCAM from rat crude synaptosomes, and was localized at the excitatory synapses in rat hippocampal neurons. NPRAP/delta-catenin may be implicated in the molecular organization of synaptic junctions through the interaction with S-SCAM.

    Biochemical and biophysical research communications 1999;256;3;456-61

  • Presenilins interact with armadillo proteins including neural-specific plakophilin-related protein and beta-catenin.

    Levesque G, Yu G, Nishimura M, Zhang DM, Levesque L, Yu H, Xu D, Liang Y, Rogaeva E, Ikeda M, Duthie M, Murgolo N, Wang L, VanderVere P, Bayne ML, Strader CD, Rommens JM, Fraser PE and St George-Hyslop P

    Centre for Research in Neurodegenerative Diseases, Department of Medicine (Neurology), University of Toronto, and Toronto Hospital, Ontario, Canada.

    Missense substitutions in the presenilin 1 (PS1) and presenilin 2 (PS2) proteins are associated with early-onset familial Alzheimer's disease. We have used yeast-two-hybrid and coimmunoprecipitation methods to show that the large cytoplasmic loop domains of PS1 and PS2 interact specifically with three members of the armadillo protein family, including beta-catenin, p0071, and a novel neuronal-specific armadillo protein--neural plakophilin-related armadillo protein (NPRAP). The PS1:NPRAP interaction occurs between the arm repeats of NPRAP and residues 372-399 at the C-terminal end of the large cytoplasmic loop of PS1. The latter residues contain a single arm-like domain and are highly conserved in the presenilins, suggesting that they form a functional armadillo protein binding site for the presenilins.

    Funded by: Canadian Institutes of Health Research: 37920

    Journal of neurochemistry 1999;72;3;999-1008

  • Isolation of human delta-catenin and its binding specificity with presenilin 1.

    Tanahashi H and Tabira T

    Division of Demyelinating Disease and Aging, National Institute of Neuroscience, Kodaira, Tokyo, Japan.

    We screened proteins for interaction with presenilin (PS) 1, and cloned the full-length cDNA of human delta-catenin, which encoded 1225 amino acids. Yeast two-hybrid assay, GST binding assay and immunoprecipitation demonstrated that delta-catenin interacted with a hydrophilic loop region in the endoproteolytic C-terminal fragment of PS1, but not with that of PS-2. These results suggest that PS1 and PS2 partly differ in function. PS1 loop fragment containing the pathogenic mutation retained the binding ability. We also found another armadillo-protein, p0071, interacted with PS1.

    Neuroreport 1999;10;3;563-8

  • delta-catenin, an adhesive junction-associated protein which promotes cell scattering.

    Lu Q, Paredes M, Medina M, Zhou J, Cavallo R, Peifer M, Orecchio L and Kosik KS

    Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    The classical adherens junction that holds epithelial cells together consists of a protein complex in which members of the cadherin family linked to various catenins are the principal components. delta-catenin is a mammalian brain protein in the Armadillo repeat superfamily with sequence similarity to the adherens junction protein p120(ctn). We found that delta-catenin can be immunoprecipitated as a complex with other components of the adherens junction, including cadherin and beta-catenin, from transfected cells and brain. The interaction with cadherin involves direct contact within the highly conserved juxtamembrane region of the COOH terminus, where p120(ctn) also binds. In developing mouse brain, staining with delta-catenin antibodies is prominent towards the apical boundary of the neuroepithelial cells in the ventricular zone. When transfected into Madin-Darby canine kidney (MDCK) epithelial cells delta-catenin colocalized with cadherin, p120(ctn), and beta-catenin. The Arm domain alone was sufficient for achieving localization and coimmunoprecipitation with cadherin. The ectopic expression of delta-catenin in MDCK cells altered their morphology, induced the elaboration of lamellipodia, interfered with monolayer formation, and increased scattering in response to hepatocyte growth factor treatment. We propose that delta-catenin can regulate adhesion molecules to implement the organization of large cellular arrays necessary for tissue morphogenesis.

    Funded by: NIA NIH HHS: AG06601; NIGMS NIH HHS: GM47857

    The Journal of cell biology 1999;144;3;519-32

  • Chromosomal mapping of human armadillo genes belonging to the p120(ctn)/plakophilin subfamily.

    Bonné S, van Hengel J and van Roy F

    Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Gent, Belgium.

    Armadillo-like proteins are characterized by a series of armadillo repeats that are typically 42 to 45 amino acids in length. Three major subfamilies of Armadillo-like proteins can be distinguished on the basis of their number of repeats, their overall sequence similarity, and dispersion of the repeats throughout the protein. One of these is the p120(ctn)/plakophilin subfamily, which contains at least six members. We mapped the corresponding human genes by PCR on a monochromosomal cell hybrid mapping panel and by fluorescence in situ hybridization. The gene for plakophilin-1 (PKP1) was located at 1q32, the plakophilin-2 gene (PKP2) was located at 12p13, while the gene for p0071 was located at 2q23-q31. We confirmed the chromosomal localization of the p120(ctn) gene (CTNND1) at 11q11, the ARVCF gene at 22q11, and the delta-catenin/NPRAP gene (CTNND2) at 5p15. Although some of the Armadillo proteins are highly related to one another, the corresponding genes are dispersed throughout the human genome.

    Genomics 1998;51;3;452-4

  • Identification and localization of a neurally expressed member of the plakoglobin/armadillo multigene family.

    Paffenholz R and Franke WW

    Division of Cell Biology, German Cancer Research Center, Heidelberg, Germany.

    The plakoglobin/armadillo multigene family comprises many proteins widely differing in sizes and functions which have in common a variable number of tandemly repeated arm sequences of about 42 amino acids (aa). In a search for proteins with sequence homology to the desmosomal-plaque-associated arm-repeat-containing protein, plakophilin 1, we have identified a novel plakoglobin/armadillo protein. This new member of the multigene family is predominantly, if not exclusively, expressed in neural and neuroendocrine tissues, hence the name neural plakophilin-related arm-repeat protein (NPRAP). The murine cDNA codes for a protein of 1247 aa, with a predicted molecular weight of 135 kDa and a pI of 7.57. The orthologous human protein differs only in a few aa, indicative of the evolutionary stability of NPRAP. In human and murine cDNAs, we have found different transcripts of the NPRAP gene, suggesting that in each species the protein exists in at least two isoforms. The NPRA protein contains three different regions: a 528-aa amino-terminal "head" domain, including a potential coiled-coil-forming alpha-helix segment, a central domain with 10 imperfect arm-repeat units, and a 212-aa carboxy-terminal "tail" domain. By aa sequence, NPRAP is highly homologous to three proteins: p120cas, p0071 and ARVCP, which represent a distinct subgroup within the plakoglobin/armadillo family. By in situ hybridization and immunofluorescence microscopy using NPRAP-specific antibodies, we have demonstrated NPRAP and its mRNA in the perikarya of various kinds of CNS neurons in embryonic and adult mice, but minimal amounts have also been detected by immunoblot analysis in some other tissues containing neural or neuroendocrine elements. We have not seen significant enrichment of NPRAP at cell junctions or in nuclei. Possible NPRAP functions are discussed and the correlation of NPRAP synthesis with neuronal differentiation processes is emphasized.

    Differentiation; research in biological diversity 1997;61;5;293-304

  • Presenilin 1 interaction in the brain with a novel member of the Armadillo family.

    Zhou J, Liyanage U, Medina M, Ho C, Simmons AD, Lovett M and Kosik KS

    Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.

    One approach to understanding the function of presenilin 1 (PS1), is to discover those proteins with which it interacts. Evidence for a function in developmental patterning came from C. elegans, in which a PS homologue was identified by screening for suppressors of a mutation in Notch/lin-12, a gene which specifies cell fate. However, this genetic experiment cannot determine which proteins directly interact with PS1. Therefore, we utilized the two hybrid system and confirmatory co-immunoprecipitations to identify a novel catenin, termed delta-catenin, which interacts with PS1 and is principally expressed in brain. The catenins are a gene family related to the Armadillo gene in Drosophila, some of which appear to have dual roles-they are components of cell-cell adherens junctions, and may serve as intermediates in the Wingless (Wg) signaling pathway, which, like Notch/lin-12, is also responsible for a variety of inductive signaling events. In the non-neuronal 293 cell line, PS1 interacted with beta-catenin, the family member with the greatest homology to Armadillo. Wg and Notch interactions are mediated by the Dishevelled gene, which may form a signaling complex with PS1 and Wg pathway intermediates to regulate the function of the Notch/lin-12 gene.

    Neuroreport 1997;8;8;2085-90

  • Large-scale concatenation cDNA sequencing.

    Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G and Gibbs RA

    A total of 100 kb of DNA derived from 69 individual human brain cDNA clones of 0.7-2.0 kb were sequenced by concatenated cDNA sequencing (CCS), whereby multiple individual DNA fragments are sequenced simultaneously in a single shotgun library. The method yielded accurate sequences and a similar efficiency compared with other shotgun libraries constructed from single DNA fragments (> 20 kb). Computer analyses were carried out on 65 cDNA clone sequences and their corresponding end sequences to examine both nucleic acid and amino acid sequence similarities in the databases. Thirty-seven clones revealed no DNA database matches, 12 clones generated exact matches (> or = 98% identity), and 16 clones generated nonexact matches (57%-97% identity) to either known human or other species genes. Of those 28 matched clones, 8 had corresponding end sequences that failed to identify similarities. In a protein similarity search, 27 clone sequences displayed significant matches, whereas only 20 of the end sequences had matches to known protein sequences. Our data indicate that full-length cDNA insert sequences provide significantly more nucleic acid and protein sequence similarity matches than expressed sequence tags (ESTs) for database searching.

    Funded by: NHGRI NIH HHS: 1F32 HG00169-01, P30 HG00210-05, R01 HG00823

    Genome research 1997;7;4;353-8

  • Isolation of cDNAs from the Cri-du-chat critical region by direct screening of a chromosome 5-specific cDNA library.

    Simmons AD, Overhauser J and Lovett M

    Department of Otorhinolaryngology, University of Texas Southwestern Medical Center at Dallas 75235, USA.

    Chromosome-specific cDNA libraries are new tools for the isolation of genes from specific genomic regions. We have used two YACs than span the approximately 2-Mb cri-du-chat critical region (CDCCR) of chromosome 5p to directly screen a chromosome 5-specific (CH5SP) fetal brain cDNA library. To compare this library with other sources for new gene discovery, the YACs were hybridized to a normalized infant brain (NIB) cDNA library that has been used extensively for expressed sequence tag (EST) generation. These screens yielded 12 cDNAs from the CH5SP fetal brain library and four cDNAs from the NIB library that mapped to discrete intervals within the CDCCR. Four cDNAs mapped within the minimal CDCCR deletion interval, with the remaining cDNAs being located beyond the boundaries. Only one cDNA shared sequence overlap between the CH5SP and NIB sets of clones. None of the remaining 11 CH5SP cDNAs were homologous to EST sequences, suggesting, in common with previous data on these libraries, that chromosome-specific cDNA libraries are a rich source of new expressed sequences. The single cDNA that did overlap with the NIB library contained two copies of a sequence motif shared with thrombospondin, properdin, and several complement proteins. This motif is usually present in adhesive proteins, and appears to mediate cell-cell or cell-substrate interactions. This new thrombospondin-like gene, and the other three cDNAs that map within the CDCCR, represent candidate genes for the cri-du-chat contiguous gene deletion syndrome.

    Funded by: NHGRI NIH HHS: HG00038, HG00236, HG00368

    Genome research 1997;7;2;118-27

  • A "double adaptor" method for improved shotgun library construction.

    Andersson B, Wentland MA, Ricafrente JY, Liu W and Gibbs RA

    Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA.

    The efficiency of shotgun DNA sequencing depends to a great extent on the quality of the random-subclone libraries used. We here describe a novel "double adaptor" strategy for efficient construction of high-quality shotgun libraries. In this method, randomly sheared and end-repaired fragments are ligated to oligonucleotide adaptors creating 12-base overhangs. Nonphosphorylated oligonucleotides are used, which prevents formation of adaptor dimers and ensures efficient ligation of insert to adaptor. The vector is prepared from a modified M13 vector, by KpnI/PstI digestion followed by ligation to oligonucleotides with ends complementary to the overhangs created in the digest. These adaptors create 5'-overhangs complementary to those on the inserts. Following annealing of insert to vector, the DNA is directly used for transformation without a ligation step. This protocol is robust and shows three- to fivefold higher yield of clones compared to previous protocols. No chimeric clones can be detected and the background of clones without an insert is <1%. The procedure is rapid and shows potential for automation.

    Funded by: NHGRI NIH HHS: R01 HG00823

    Analytical biochemistry 1996;236;1;107-13

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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