CDH2

Cadherin 2, type 1, N-cadherin (neuronal)
PDB rendering based on 1ncg.
Identifiers
Symbols	CDH2 ; CD325; CDHN; CDw325; NCAD
External IDs	OMIM: 114020 MGI: 88355 HomoloGene: 20424 ChEMBL: 1697669 GeneCards: CDH2 Gene
Gene ontology Molecular function • calcium ion binding • protein binding • beta-catenin binding • protein kinase binding • protein phosphatase binding • protein complex binding • alpha-catenin binding • gamma-catenin binding • nitric-oxide synthase binding Cellular component • cytoplasm • plasma membrane • cell-cell junction • cell-cell adherens junction • fascia adherens • focal adhesion • intercalated disc • integral component of membrane • basolateral plasma membrane • apical plasma membrane • catenin complex • lamellipodium • cortical actin cytoskeleton • synapse • extracellular exosome Biological process • cell adhesion • homophilic cell adhesion via plasma membrane adhesion molecules • heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules • glial cell differentiation • calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules • cell migration • regulation of myelination • cell junction assembly • adherens junction organization • regulation of Rho protein signal transduction • muscle cell differentiation • positive regulation of MAPK cascade • cell-cell adhesion mediated by cadherin • cell-cell junction organization • blood vessel morphogenesis • regulation of axonogenesis • striated muscle cell differentiation • positive regulation of muscle cell differentiation • protein heterooligomerization • negative regulation of canonical Wnt signaling pathway • neuroligin clustering involved in postsynaptic membrane assembly • neuronal stem cell maintenance • regulation of postsynaptic density protein 95 clustering • positive regulation of synaptic vesicle clustering Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1000	12558
Ensembl	ENSG00000170558	ENSMUSG00000024304
UniProt	P19022	P15116
RefSeq (mRNA)	NM_001308176	NM_007664
RefSeq (protein)	NP_001295105	NP_031690
Location (UCSC)	Chr 18: 27.95 – 28.18 Mb	Chr 18: 16.59 – 16.81 Mb
PubMed search

N-cadherin, also known as Cadherin-2 (CDH2) or neural cadherin (NCAD) is a protein that in humans is encoded by the CDH2 gene.^[1][2] CDH2 has also been designated as CD325 (cluster of differentiation 325). N-cadherin is a transmembrane protein expressed in multiple tissues and functions to mediate cell-cell adhesion. In cardiac muscle, N-cadherin is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. While mutations in CDH2 have not thus far been associated with human disease, alterations in expression and integrity of N-cadherin protein has been observed in various forms of disease, including human dilated cardiomyopathy.

Structure

N-cadherin is a protein with molecular weight of 99.7 kDa, and 906 amino acids in length.^[3] N-cadherin a classical cadherin from the cadherin superfamily, composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. N-cadherin, as well as other cadherins, interact with N-cadherin on an adjacent cell in an anti-parallel conformation, thus creating a linear, adhesive "zipper" between cells.^[4]

Function

N-cadherin, originally named for its role in neural tissue, plays a role in neurons and later was found to also play a role in cardiac muscle and in cancer metastasis. N-cadherin is a transmembrane, homophilic glycoprotein belonging to the calcium-dependent cell adhesion molecule family. These proteins have extracellular domains that mediate homophilic interactions between adjacent cells, and C-terminal, cytoplasmic tails that mediate binding to catenins, which in turn interact with the actin cytoskeleton.^[5][6][7]

Role in development

N-cadherin plays a role in development as a calcium dependent cell-cell adhesion glycoprotein that functions during gastrulation and is required for establishment of left-right asymmetry.^[8]

N-cadherin is widely expressed in the embryo post-implantation, showing high levels in the mesoderm with sustained expression through adulthood.^[9] N-cadherin mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociated myocytes and abnormal heart tube development occur.^[10] N-cadherin plays a role in the development of the vertebrate heart at the transition of epithelial cells to trabecular and compact myocardial cell layer formation.^[11] An additional study showed that myocytes expressing a dominant negative N-cadherin mutant showed significant abnormalities in myocyte distribution and migration towards the endocardium, resulting in defects in trabecular formation within the myocardium.^[12][13]

Role in cardiac muscle

In cardiac muscle, N-cadherin is found at intercalated disc structures which provide end-on cell-cell connections that facilitate mechanical and electrical coupling between adjacent cardiomyocytes. Within intercalated discs are three types of junctions: adherens junctions, desmosomes and gap junctions;^[14] N-cadherin is an essential component in adherens junctions, which enables cell-cell adhesion and force transmission across the sarcolemma.^[15] N-cadherin complexed to catenins has been described as a master regulator of intercalated disc function.^[16] N-cadherin appears at cell-cell junctions prior to gap junction formation,^[17][18] and is critical for normal myofibrillogenesis.^[19] Expression of a mutant form of N-cadherin harboring a large deletion in the extracellular domain inhibited the function of endogenous N-cadherin in adult ventricular cardiomyocytes, and neighboring cardiomyocytes lost cell-cell contact and gap junction plaques as well.^[20]

Mouse models employing transgenesis have highlighted the function of N-cadherin in cardiac muscle. Mice with altered expression of N-cadherin and/or E-cadherin showed a dilated cardiomyopathy phenotype, likely due to malfunction of intercalated discs.^[21] In agreement with this, mice with ablation of N-cadherin in adult hearts via a cardiac-specific tamoxifen-inducible Cre N-cadherin transgene showed disrupted assembly of intercalated discs, dilated cardiomyopathy, impaired cardiac function, decreased sarcomere length, increased Z-line thickness, decreases in connexin 43, and a loss in muscular tension. Mice died within two months of transgene expression, mainly due to spontaneous ventricular tachycardia.^[22] Further analysis of N-cadherin knockout mice revealed that the arrhythmias were likely due to ion channel remodeling and aberrant Kv1.5 channel function. These animals showed a prolonged action potential duration, reduced density of inward rectifier potassium channel and decreased expression of Kv1.5, KCNE2 and cortactin combined with disrupted actin cytoskeleton at the sarcolemma.^[23]

Role in neurons

In neural cells, at certain central nervous system synapses, presynaptic to postsynaptic adhesion is mediated at least in part by N-cadherin.^[24] N-cadherins interact with catenins to play an important role in learning and memory (For full article see Cadherin-catenin complex in learning and memory).

Role in cancer metastasis

N-Cadherin is commonly found in cancer cells and provides a mechanism for transendothelial migration. When a cancer cell adheres to the endothelial cells of a blood vessel it up-regulates the src kinase pathway, which phosphorylates beta-catenins attached to both N-cadherin (this protein) and E-cadherins. This causes the intercellular connection between two adjacent endothelial cells to fail and allows the cancer cell to slip through.^[25]

Clinical Significance

Mutations in CDH2 have not been conclusively linked to any human disorders. One study investigating genetic underpinnings of obsessive-compulsive disorder and Tourette disorder found that while CDH2 variants are likely not disease-causing as single entities, they may confer risk when examined as part of a panel of related cell-cell adhesion genes.^[26] Further studies in larger cohorts will be required to unequivocally determine this.

In human dilated cardiomyopathy, it was shown that N-cadherin expression was enhanced and arranged in a disarrayed fashion, suggesting that disorganization of N-cadherin protein in heart disease may be a component of remodeling.^[27]

Interactions

CDH2 has been shown to interact with:

• Beta-catenin,^[28][29]
• CDH11,^[28]
• type IIb RPTPs including PTPmu (CTNND1),^[28][29]
• CTNNA1,^[28][29]
• LRRC7,^[30]
• PTPRM)^[31][32]
• PTPrho (PTPRT),^[33] and
• Plakoglobin.^[28][34]
• XIRP1^[35]
• SCARB2 ^[36]

References

1. Walsh FS, Barton CH, Putt W, Moore SE, Kelsell D, Spurr N, Goodfellow PN (September 1990). "N-cadherin gene maps to human chromosome 18 and is not linked to the E-cadherin gene". J. Neurochem. 55 (3): 805–12. doi:10.1111/j.1471-4159.1990.tb04563.x. PMID 2384753.
2. Reid RA, Hemperly JJ (October 1990). "Human N-cadherin: nucleotide and deduced amino acid sequence". Nucleic Acids Res. 18 (19): 5896–5896. doi:10.1093/nar/18.19.5896. PMC 332345. PMID 2216790.
3. "Protein sequence of human CDH2 (Uniprot ID: P19022)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 20 July 2015.
4. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grübel G, Legrand JF, Als-Nielsen J, Colman DR, Hendrickson WA (Mar 1995). "Structural basis of cell-cell adhesion by cadherins". Nature 374 (6520): 327–37. doi:10.1038/374327a0. PMID 7885471.
5. Buxton RS, Magee AI (Jun 1992). "Structure and interactions of desmosomal and other cadherins". Seminars in Cell Biology 3 (3): 157–67. doi:10.1016/s1043-4682(10)80012-1. PMID 1623205.
6. Takeichi M (1990). "Cadherins: a molecular family important in selective cell-cell adhesion". Annual Review of Biochemistry 59: 237–52. doi:10.1146/annurev.bi.59.070190.001321. PMID 2197976.
7. Ozawa M, Baribault H, Kemler R (Jun 1989). "The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species". The EMBO Journal 8 (6): 1711–7. PMC 401013. PMID 2788574.
8. García-Castro MI, Vielmetter E, Bronner-Fraser M (May 2000). "N-Cadherin, a cell adhesion molecule involved in establishment of embryonic left-right asymmetry". Science 288 (5468): 1047–51. doi:10.1126/science.288.5468.1047. PMID 10807574.
9. Angst BD, Khan LU, Severs NJ, Whitely K, Rothery S, Thompson RP, Magee AI, Gourdie RG (Jan 1997). "Dissociated spatial patterning of gap junctions and cell adhesion junctions during postnatal differentiation of ventricular myocardium". Circulation Research 80 (1): 88–94. doi:10.1161/01.res.80.1.88. PMID 8978327.
10. Radice GL, Rayburn H, Matsunami H, Knudsen KA, Takeichi M, Hynes RO (Jan 1997). "Developmental defects in mouse embryos lacking N-cadherin". Developmental Biology 181 (1): 64–78. doi:10.1006/dbio.1996.8443. PMID 9015265.
11. Kostetskii I, Moore R, Kemler R, Radice GL (Jun 2001). "Differential adhesion leads to segregation and exclusion of N-cadherin-deficient cells in chimeric embryos". Developmental Biology 234 (1): 72–9. doi:10.1006/dbio.2001.0250. PMID 11356020.
12. Linask KK, Knudsen KA, Gui YH (May 1997). "N-cadherin-catenin interaction: necessary component of cardiac cell compartmentalization during early vertebrate heart development". Developmental Biology 185 (2): 148–64. doi:10.1006/dbio.1997.8570. PMID 9187080.
13. Ong LL, Kim N, Mima T, Cohen-Gould L, Mikawa T (Jan 1998). "Trabecular myocytes of the embryonic heart require N-cadherin for migratory unit identity". Developmental Biology 193 (1): 1–9. doi:10.1006/dbio.1997.8775. PMID 9466883.
14. Peters NS, Severs NJ, Rothery SM, Lincoln C, Yacoub MH, Green CR (Aug 1994). "Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium". Circulation 90 (2): 713–25. doi:10.1161/01.cir.90.2.713. PMID 8044940.
15. Forbes MS, Sperelakis N (1985). "Intercalated discs of mammalian heart: a review of structure and function". Tissue & Cell 17 (5): 605–48. doi:10.1016/0040-8166(85)90001-1. PMID 3904080.
16. Vite, A; Radice, GL (June 2014). "N-cadherin/catenin complex as a master regulator of intercalated disc function.". Cell communication & adhesion 21 (3): 169–79. doi:10.3109/15419061.2014.908853. PMID 24766605.
17. Zuppinger C, Schaub MC, Eppenberger HM (Apr 2000). "Dynamics of early contact formation in cultured adult rat cardiomyocytes studied by N-cadherin fused to green fluorescent protein". Journal of Molecular and Cellular Cardiology 32 (4): 539–55. doi:10.1006/jmcc.1999.1086. PMID 10756112.
18. Dou, JP; Jiao, B; Sheng, JJ; Yu, ZB (25 October 2014). "[Dynamic assembly of intercalated disc during postnatal development in the rat myocardium].". Sheng li xue bao : [Acta physiologica Sinica] 66 (5): 569–74. PMID 25332002.
19. Goncharova EJ, Kam Z, Geiger B (Jan 1992). "The involvement of adherens junction components in myofibrillogenesis in cultured cardiac myocytes". Development 114 (1): 173–83. PMID 1576958.
20. Hertig CM, Eppenberger-Eberhardt M, Koch S, Eppenberger HM (Jan 1996). "N-cadherin in adult rat cardiomyocytes in culture. I. Functional role of N-cadherin and impairment of cell-cell contact by a truncated N-cadherin mutant". Journal of Cell Science 109 (1): 1–10. PMID 8834785.
21. Ferreira-Cornwell MC, Luo Y, Narula N, Lenox JM, Lieberman M, Radice GL (Apr 2002). "Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart". Journal of Cell Science 115 (Pt 8): 1623–34. PMID 11950881.
22. Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, Molkentin JD, Radice GL (Feb 2005). "Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure". Circulation Research 96 (3): 346–54. doi:10.1161/01.RES.0000156274.72390.2c. PMID 15662031.
23. Cheng, L; Yung, A; Covarrubias, M; Radice, GL (10 June 2011). "Cortactin is required for N-cadherin regulation of Kv1.5 channel function.". The Journal of Biological Chemistry 286 (23): 20478–89. doi:10.1074/jbc.m111.218560. PMID 21507952.
24. "Entrez Gene: CDH2 cadherin 2, type 1, N-cadherin (neuronal)".
25. Ramis-Conde I, Chaplain MA, Anderson AR, Drasdo D (2009). "Multi-scale modelling of cancer cell intravasation: the role of cadherins in metastasis". Phys Biol 6 (1): 016008. doi:10.1088/1478-3975/6/1/016008. PMID 19321920.
26. Moya, PR; Dodman, NH; Timpano, KR; Rubenstein, LM; Rana, Z; Fried, RL; Reichardt, LF; Heiman, GA; Tischfield, JA; King, RA; Galdzicka, M; Ginns, EI; Wendland, JR (August 2013). "Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes.". European Journal of Human Genetics 21 (8): 850–4. doi:10.1038/ejhg.2012.245. PMID 23321619.
27. Tsipis, A; Athanassiadou, AM; Athanassiadou, P; Kavantzas, N; Agrogiannis, G; Patsouris, E (15 September 2010). "Apoptosis-related factors p53, bcl-2 and the defects of force transmission in dilated cardiomyopathy.". Pathology, research and practice 206 (9): 625–30. doi:10.1016/j.prp.2010.05.007. PMID 20591580.
28. Straub BK, Boda J, Kuhn C, Schnoelzer M, Korf U, Kempf T, Spring H, Hatzfeld M, Franke WW (Dec 2003). "A novel cell-cell junction system: the cortex adhaerens mosaic of lens fiber cells". J. Cell. Sci. 116 (Pt 24): 4985–95. doi:10.1242/jcs.00815. PMID 14625392.
29. Wahl JK, Kim YJ, Cullen JM, Johnson KR, Wheelock MJ (May 2003). "N-cadherin-catenin complexes form prior to cleavage of the proregion and transport to the plasma membrane". J. Biol. Chem. 278 (19): 17269–76. doi:10.1074/jbc.M211452200. PMID 12604612.
30. Izawa I, Nishizawa M, Ohtakara K, Inagaki M (Feb 2002). "Densin-180 interacts with delta-catenin/neural plakophilin-related armadillo repeat protein at synapses". J. Biol. Chem. 277 (7): 5345–50. doi:10.1074/jbc.M110052200. PMID 11729199.
31. Brady-Kalnay SM, Rimm DL, Tonks NK. "Receptor protein tyrosine phosphatase PTPmu associates with cadherins and catenins in vivo". J. Cell Biol. 130 (4): 977–86. doi:10.1083/jcb.130.4.977. PMC 2199947. PMID 7642713.
32. Brady-Kalnay SM, Mourton T, Nixon JP, Pietz GE, Kinch M, Chen H, Brackenbury R, Rimm DL, Del Vecchio RL, Tonks NK. "Dynamic interaction of PTPmu with multiple cadherins in vivo". J. Cell Biol. 141 (1): 287–96. doi:10.1083/jcb.141.1.287. PMC 2132733. PMID 9531566.
33. Besco JA, Hooft van Huijsduijnen R, Frostholm A, Rotter A (Oct 2006). "Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT)". Brain Res. 1116 (1): 50–7. doi:10.1016/j.brainres.2006.07.122. PMID 16973135.
34. Sacco PA, McGranahan TM, Wheelock MJ, Johnson KR (Aug 1995). "Identification of plakoglobin domains required for association with N-cadherin and alpha-catenin". J. Biol. Chem. 270 (34): 20201–6. doi:10.1074/jbc.270.34.20201. PMID 7650039.
35. Sinn HW, Balsamo J, Lilien J, Lin JJ (Sep 2002). "Localization of the novel Xin protein to the adherens junction complex in cardiac and skeletal muscle during development". Developmental Dynamics 225 (1): 1–13. doi:10.1002/dvdy.10131. PMID 12203715.
36. Schroen B, Leenders JJ, van Erk A, Bertrand AT, van Loon M, van Leeuwen RE, Kubben N, Duisters RF, Schellings MW, Janssen BJ, Debets JJ, Schwake M, Høydal MA, Heymans S, Saftig P, Pinto YM (May 2007). "Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy". The Journal of Experimental Medicine 204 (5): 1227–35. doi:10.1084/jem.20070145. PMID 17485520.

Further reading

• Doherty P, Smith P, Walsh FS (1997). "Shared cell adhesion molecule (CAM) homology domains point to CAMs signalling via FGF receptors". Perspectives on developmental neurobiology 4 (2–3): 157–68. PMID 9168198.
• Makrigiannakis A, Coukos G, Blaschuk O, Coutifaris C (2000). "Follicular atresia and luteolysis. Evidence of a role for N-cadherin". Ann. N. Y. Acad. Sci. 900: 46–55. doi:10.1111/j.1749-6632.2000.tb06215.x. PMID 10818391.
• Hazan RB, Qiao R, Keren R, Badano I, Suyama K (2004). "Cadherin switch in tumor progression". Ann. N. Y. Acad. Sci. 1014: 155–63. doi:10.1196/annals.1294.016. PMID 15153430.
• Cavallaro U (2005). "N-cadherin as an invasion promoter: a novel target for antitumor therapy?". Current opinion in investigational drugs (London, England : 2000) 5 (12): 1274–8. PMID 15648948.
• Salomon D, Ayalon O, Patel-King R, Hynes RO, Geiger B (1992). "Extrajunctional distribution of N-cadherin in cultured human endothelial cells". J. Cell. Sci. 102 (1): 7–17. PMID 1500442.
• Knudsen KA, Wheelock MJ (1992). "Plakoglobin, or an 83-kD homologue distinct from beta-catenin, interacts with E-cadherin and N-cadherin". J. Cell Biol. 118 (3): 671–9. doi:10.1083/jcb.118.3.671. PMC 2289540. PMID 1639850.
• Reid RA, Hemperly JJ (1990). "Human N-cadherin: nucleotide and deduced amino acid sequence". Nucleic Acids Res. 18 (19): 5896–5896. doi:10.1093/nar/18.19.5896. PMC 332345. PMID 2216790.
• Walsh FS, Barton CH, Putt W, Moore SE, Kelsell D, Spurr N, Goodfellow PN (1990). "N-cadherin gene maps to human chromosome 18 and is not linked to the E-cadherin gene". J. Neurochem. 55 (3): 805–12. doi:10.1111/j.1471-4159.1990.tb04563.x. PMID 2384753.
• Selig S, Bruno S, Scharf JM, Wang CH, Vitale E, Gilliam TC, Kunkel LM (1995). "Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene". Proc. Natl. Acad. Sci. U.S.A. 92 (9): 3702–6. doi:10.1073/pnas.92.9.3702. PMC 42029. PMID 7731968.
• Wallis J, Fox MF, Walsh FS (1994). "Structure of the human N-cadherin gene: YAC analysis and fine chromosomal mapping to 18q11.2". Genomics 22 (1): 172–9. doi:10.1006/geno.1994.1358. PMID 7959764.
• Andersson AM, Edvardsen K, Skakkebaek NE (1995). "Expression and localization of N- and E-cadherin in the human testis and epididymis". Int. J. Androl. 17 (4): 174–80. doi:10.1111/j.1365-2605.1994.tb01239.x. PMID 7995652.
• Matsuyoshi N, Imamura S (1997). "Multiple cadherins are expressed in human fibroblasts". Biochem. Biophys. Res. Commun. 235 (2): 355–8. doi:10.1006/bbrc.1997.6707. PMID 9199196.
• Navarro P, Ruco L, Dejana E (1998). "Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization". J. Cell Biol. 140 (6): 1475–84. doi:10.1083/jcb.140.6.1475. PMC 2132661. PMID 9508779.
• Gaidar YA, Lepekhin EA, Sheichetova GA, Witt M (1998). "Distribution of N-cadherin and NCAM in neurons and endocrine cells of the human embryonic and fetal gastroenteropancreatic system". Acta Histochem. 100 (1): 83–97. doi:10.1016/s0065-1281(98)80008-1. PMID 9542583.
• Kremmidiotis G, Baker E, Crawford J, Eyre HJ, Nahmias J, Callen DF (1998). "Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity". Genomics 49 (3): 467–71. doi:10.1006/geno.1998.5281. PMID 9615235.
• Lu Q, Paredes M, Medina M, Zhou J, Cavallo R, Peifer M, Orecchio L, Kosik KS (1999). "delta-catenin, an adhesive junction-associated protein that promotes cell scattering". J. Cell Biol. 144 (3): 519–32. doi:10.1083/jcb.144.3.519. PMC 2132907. PMID 9971746.
• Shan WS, Tanaka H, Phillips GR, Arndt K, Yoshida M, Colman DR, Shapiro L (2000). "Functional cis-heterodimers of N- and R-cadherins". J. Cell Biol. 148 (3): 579–90. doi:10.1083/jcb.148.3.579. PMC 2174798. PMID 10662782.
• Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000). "Proteomic analysis of NMDA receptor-adhesion protein signaling complexes". Nat. Neurosci. 3 (7): 661–9. doi:10.1038/76615. PMID 10862698.

External links

• CDH2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• CDH2 human gene location in the UCSC Genome Browser.
• CDH2 human gene details in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.