Plakoglobin

JUP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3IFQ
Identifiers
Aliases	JUP, ARVD12, CTNNG, DP3, DPIII, PDGB, PKGB, Plakoglobin, junction plakoglobin, PG
External IDs	OMIM: 173325; MGI: 96650; HomoloGene: 1680; GeneCards: JUP; OMA:JUP - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q21.2 Start 41,754,604 bp[1] End 41,786,931 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 D|11 63.47 cM Start 100,259,784 bp[2] End 100,288,589 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in skin of leg skin of abdomen mucosa of pharynx nipple gingival epithelium skin of arm human penis vulva skin of thigh apex of heart Top expressed in lip esophagus corneal stroma skin of back muscle of thigh skin of external ear stomach pyloric antrum epithelium of stomach yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity transcription coactivator activity structural constituent of cell wall structural molecule activity signal transducer activity protein binding cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication protein phosphatase binding protein kinase binding alpha-catenin binding cell adhesion molecule binding cadherin binding Cellular component cytoplasm cytosol gamma-catenin-TCF7L2 complex lateral plasma membrane membrane intercalated disc cell-cell junction focal adhesion adherens junction plasma membrane desmosome hemidesmosome cell junction apicolateral plasma membrane protein-DNA complex Z discdkac actin cytoskeleton zonula adherens cytoplasmic side of plasma membrane catenin complex fascia adherens cytoskeleton intermediate filament extracellular exosome nucleus extracellular matrix cornified envelope extracellular region specific granule lumen ficolin-1-rich granule lumen Biological process adherens junction assembly protein heterooligomerization positive regulation of canonical Wnt signaling pathway positive regulation of DNA-binding transcription factor activity bundle of His cell-Purkinje myocyte adhesion involved in cell communication endothelial cell-cell adhesion cellular response to indole-3-methanol desmosome assembly cell adhesion regulation of cell population proliferation detection of mechanical stimulus positive regulation of protein import into nucleus adherens junction organization regulation of heart rate by cardiac conduction cell migration regulation of ventricular cardiac muscle cell action potential skin development signal transduction keratinization neutrophil degranulation cornification protein localization to plasma membrane cell-cell adhesion positive regulation of cell-matrix adhesion negative regulation of blood vessel endothelial cell migration positive regulation of angiogenesis positive regulation of transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3728 16480 Ensembl ENSG00000173801 ENSMUSG00000001552 UniProt P14923 Q02257 RefSeq (mRNA) NM_002230 NM_021991 NM_001352773 NM_001352774 NM_001352775 NM_001352776 NM_001352777 NM_010593 RefSeq (protein) NP_002221 NP_068831 NP_001339702 NP_001339703 NP_001339704 NP_001339705 NP_001339706 NP_034723 Location (UCSC) Chr 17: 41.75 – 41.79 Mb Chr 11: 100.26 – 100.29 Mb PubMed search [3] [4]
Wikidata
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Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene.^[5] Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.

Structure

Human plakoglobin is 81.7 kDa in molecular weight and 745 amino acids long.^[6] The JUP gene contains 13 exons spanning 17 kb on chromosome 17q21.^[7] Plakoglobin is a member of the catenin family, since it contains a distinct repeating amino acid motif called the armadillo repeat.^[5] Plakoglobin is highly similar to β-catenin; both have 12 armadillo repeats as well as N-terminal and C-terminal globular domains of unknown structure.^[8] Plakoglobin was originally identified as a component of desmosomes, where it can bind to the cadherin family member desmoglein I. Plakoglobin also associates with classical cadherins such as E-cadherin; in that context, it was called gamma-catenin. Plakoglobin forms distinct complexes with cadherins and desmosomal cadherins.

Function

Plakoglobin is a major cytoplasmic component of both desmosomes and adherens junctions, and is the only known constituent common to submembranous plaques in both of these structures,^[9] which are located at the intercalated disc (ICD) of cardiomyocytes. Plakoglobin links cadherins to the actin cytoskeleton. Plakoglobin binds to conserved regions of desmoglein and desmocollin at intracellular catenin-binding sites to assemble desmosomes.^[10][11]

Plakoglobin is essential for normal development of intercalated discs and stability of cardiac muscle. Transgenic mice homozygous for a null mutation of the JUP gene die around embryonic day 12 from substantial defects in adherens junctions and a lack of functional desmosomes in the heart.^[12][13] Further studies showed that cardiac fibers obtained from JUP-null embryonic mice had decreased passive compliance albeit normal attachment of sarcomeres to adherens junctions.^[14]

In additional studies, an inducible cardiac-specific plakoglobin knockout mice were generated. Transgenic mice displayed a similar phenotype as arrhythmogenic right ventricular cardiomyopathy patients, with loss of cardiomyocytes, fibrosis and cardiac dysfunction, as well as alterations in desmosome protein content and gap junction remodeling. Hearts also exhibited increases in β-catenin signaling.^[15][16] Further investigations on the role of β-catenin and plakoglobin in the heart generated a double knockout of these two proteins. Mice exhibited cardiomyopathy, fibrosis, conduction abnormalities and sudden cardiac death, presumably via spontaneous lethal ventricular arrhythmias. Mice also showed a decrease in gap junction structures at intercalated discs.^[17]

Intracellular plakoglobin expression is controlled by Wnt signaling and ubiquitin-proteasome-dependent degradation. Phosphorylation of N-terminal Serines by a “destruction complex” composed of glycogen synthase kinase 3β (GSK3β) and scaffold proteins adenomatous polyposis coli (APC) and axin targets plakoglobin for degradation.^[18][19][20][31–33]. The phosphorylated motif is recognized by β-TrCP, a ubiquitin ligase that targets plakoglobin 26S proteasome-dependent degradation.^[21] Plakoglobin is also O-glycosylated near its N-terminal destruction box.

Clinical significance

Mutation of the JUP gene encoding plakoglobin has been implicated as one of the causes of the cardiomyopathy known as arrhythmogenic right ventricular dysplasia (ARVD) or arrhythmogenic right ventricular cardiomyopathy; mutations in JUP specifically causes an autosomal recessive form referred to as Naxos disease.^[22][23][24] This form of was first identified in a small cluster of families on the Greek island of Naxos. The phenotype of the Naxos disease variant of ARVD is unique in that it involves the hair and skin as well as the right ventricle. Affected individuals have kinky, wooly hair; there is also palmar and plantar erythema at birth that progresses to keratosis as the palms and soles of the feet are used in crawling and walking.^[25][26][27] These findings co-segregate 100% with the development of ARVD by early adolescence.

It has become clear that ARVD/ARVC is a disease of the cardiac muscle desmosome; advances in molecular genetics have illuminated this notion.^{[28][29][30][31][32][33][34][35][36]}

Studies investigating the role of plakoglobin in disease pathology have found that suppression of desmoplakin expression by siRNA led to the nuclear localization of plakoglobin, resulting in a reduction in Wnt signaling via Tcf/Lef1 and ensued pathogenesis of ARVC.^[37] Specifically, adipogenic factor expression was induced and cardiac progenitor cells at the epicardium were differentiated to adipocytes.^[38]

Non-invasive cardiac screening identified T-wave inversion, abnormalities in right ventricular wall motion, and frequent ventricular extrasystoles as sensitive and specific markers of a JUP mutation.^[39] Additional studies have shown that immunohistochemical analysis of cardiac muscle desmosomal proteins is also a sensitive and specific diagnostic text for ARVD/ARVC.^[40]

Abnormal distribution of plakoglobin due to mutations in genes encoding for Desmoglein 1 and 3 have also been implicated in Pemphigus vulgaris.^[41][42]

Interactions

Plakoglobin has been shown to interact with:

• APC,^[43][44]
• CTNNA1,^[45][46][47]
• CTNNB1,^[48][49]
• CDH1,^{[43][48][50][51][52]}
• CDH2,^[45][53]
• CDH3,^[54]
• CDH5,^[55][56]
• DSG2,^[57][58][59]
• DSP,^[60][61]
• MUC1,^[62]
• PKP2,^[63]
• PTPkappa (PTPRK),^[64]
• PTPrho (PTPRT),^[65] and
• PDLIM3.^[66]

See also

• Catenin
• List of conditions caused by problems with junctional proteins

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000001552 – Ensembl, May 2017
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Further reading

• Cowin P, Kapprell HP, Franke WW, Tamkun J, Hynes RO (Sep 1986). "Plakoglobin: a protein common to different kinds of intercellular adhering junctions". Cell. 46 (7): 1063–73. doi:10.1016/0092-8674(86)90706-3. PMID 3530498. S2CID 45332970.
• Franke WW, Goldschmidt MD, Zimbelmann R, Mueller HM, Schiller DL, Cowin P (Jun 1989). "Molecular cloning and amino acid sequence of human plakoglobin, the common junctional plaque protein". Proceedings of the National Academy of Sciences of the United States of America. 86 (11): 4027–31. Bibcode:1989PNAS...86.4027F. doi:10.1073/pnas.86.11.4027. PMC 287381. PMID 2726765.
• Mathur M, Goodwin L, Cowin P (May 1994). "Interactions of the cytoplasmic domain of the desmosomal cadherin Dsg1 with plakoglobin". The Journal of Biological Chemistry. 269 (19): 14075–80. doi:10.1016/S0021-9258(17)36756-X. PMID 8188687.
• Beavon IR (Aug 2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". European Journal of Cancer. 36 (13 Spec No): 1607–20. doi:10.1016/S0959-8049(00)00158-1. PMID 10959047.
• Wilson PD (Apr 2001). "Polycystin: new aspects of structure, function, and regulation". Journal of the American Society of Nephrology. 12 (4): 834–45. doi:10.1681/ASN.V124834. PMID 11274246.
• Protonotarios NI, Tsatsopoulou AA, Gatzoulis KA (Feb 2002). "Arrhythmogenic right ventricular cardiomyopathy caused by a deletion in plakoglobin (Naxos disease)". Cardiac Electrophysiology Review. 6 (1–2): 72–80. doi:10.1023/A:1017943323473. PMID 11984022.
• Knudsen KA, Wheelock MJ (Aug 1992). "Plakoglobin, or an 83-kD homologue distinct from beta-catenin, interacts with E-cadherin and N-cadherin". The Journal of Cell Biology. 118 (3): 671–9. doi:10.1083/jcb.118.3.671. PMC 2289540. PMID 1639850.
• Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS (Jul 1991). "Chromosomal assignment of the human genes coding for the major proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP)". Genomics. 10 (3): 640–5. doi:10.1016/0888-7543(91)90446-L. PMID 1889810.
• Kinch MS, Clark GJ, Der CJ, Burridge K (Jul 1995). "Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia". The Journal of Cell Biology. 130 (2): 461–71. doi:10.1083/jcb.130.2.461. PMC 2199929. PMID 7542250.
• Aberle H, Bierkamp C, Torchard D, Serova O, Wagner T, Natt E, Wirsching J, Heidkämper C, Montagna M, Lynch HT (Jul 1995). "The human plakoglobin gene localizes on chromosome 17q21 and is subjected to loss of heterozygosity in breast and ovarian cancers". Proceedings of the National Academy of Sciences of the United States of America. 92 (14): 6384–8. Bibcode:1995PNAS...92.6384A. doi:10.1073/pnas.92.14.6384. PMC 41522. PMID 7604000.
• Sacco PA, McGranahan TM, Wheelock MJ, Johnson KR (Aug 1995). "Identification of plakoglobin domains required for association with N-cadherin and alpha-catenin". The Journal of Biological Chemistry. 270 (34): 20201–6. doi:10.1074/jbc.270.34.20201. PMID 7650039.
• Daniel JM, Reynolds AB (Sep 1995). "The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin". Molecular and Cellular Biology. 15 (9): 4819–24. doi:10.1128/mcb.15.9.4819. PMC 230726. PMID 7651399.
• Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S (Mar 1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin". Biochemical and Biophysical Research Communications. 208 (3): 1067–72. doi:10.1006/bbrc.1995.1443. PMID 7702605.
• Roh JY, Stanley JR (May 1995). "Plakoglobin binding by human Dsg3 (pemphigus vulgaris antigen) in keratinocytes requires the cadherin-like intracytoplasmic segment". The Journal of Investigative Dermatology. 104 (5): 720–4. doi:10.1111/1523-1747.ep12606963. PMID 7738346.
• Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Miyazawa K, Kitamura N, Johnson KR, Wheelock MJ, Matsuyoshi N, Takeichi M (Mar 1995). "Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes". The Journal of Cell Biology. 128 (5): 949–57. doi:10.1083/jcb.128.5.949. PMC 2120395. PMID 7876318.
• Rubinfeld B, Souza B, Albert I, Munemitsu S, Polakis P (Mar 1995). "The APC protein and E-cadherin form similar but independent complexes with alpha-catenin, beta-catenin, and plakoglobin". The Journal of Biological Chemistry. 270 (10): 5549–55. doi:10.1074/jbc.270.10.5549. PMID 7890674.
• Troyanovsky SM, Troyanovsky RB, Eshkind LG, Leube RE, Franke WW (Nov 1994). "Identification of amino acid sequence motifs in desmocollin, a desmosomal glycoprotein, that are required for plakoglobin binding and plaque formation". Proceedings of the National Academy of Sciences of the United States of America. 91 (23): 10790–4. Bibcode:1994PNAS...9110790T. doi:10.1073/pnas.91.23.10790. PMC 45111. PMID 7971964.
• Shibata T, Gotoh M, Ochiai A, Hirohashi S (Aug 1994). "Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation". Biochemical and Biophysical Research Communications. 203 (1): 519–22. doi:10.1006/bbrc.1994.2213. PMID 8074697.
• Hinck L, Näthke IS, Papkoff J, Nelson WJ (Jun 1994). "Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly". The Journal of Cell Biology. 125 (6): 1327–40. doi:10.1083/jcb.125.6.1327. PMC 2290923. PMID 8207061.
• Arnemann J, Sullivan KH, Magee AI, King IA, Buxton RS (Mar 1993). "Stratification-related expression of isoforms of the desmosomal cadherins in human epidermis". Journal of Cell Science. 104 (3): 741–50. doi:10.1242/jcs.104.3.741. PMID 8314871.
• Ozawa M, Nuruki K, Toyoyama H, Ohi Y (Oct 1995). "Cloning of an alternative form of plakoglobin (gamma-catenin) lacking the fourth armadillo repeat". Journal of Biochemistry. 118 (4): 836–40. doi:10.1093/oxfordjournals.jbchem.a124988. PMID 8576101.
• Fuchs M, Müller T, Lerch MM, Ullrich A (Jul 1996). "Association of human protein-tyrosine phosphatase kappa with members of the armadillo family". The Journal of Biological Chemistry. 271 (28): 16712–9. doi:10.1074/jbc.271.28.16712. PMID 8663237.

External links

• GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
• OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
• gamma-Catenin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)