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Cadherin-2

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CDH2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCDH2,CD325, CDHN, CDw325, NCAD, cadherin 2, ACOGS, ARVD14
External IDsOMIM:114020;MGI:88355;HomoloGene:20424;GeneCards:CDH2;OMA:CDH2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1000

12558

Ensembl

ENSG00000170558

ENSMUSG00000024304

UniProt

P19022

P15116

RefSeq (mRNA)

NM_001308176
NM_001792

NM_007664

RefSeq (protein)

NP_001295105
NP_001783
NP_001783.2

NP_031690

Location (UCSC)Chr 18: 27.93 – 28.18 MbChr 18: 16.72 – 16.94 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cadherin-2also known asNeural cadherin(N-cadherin), is a protein that in humans is encoded by theCDH2gene.[5][6][7]CDH2 has also been designated asCD325(cluster of differentiation325). Cadherin-2 is atransmembraneproteinexpressed in multiple tissues and functions to mediate cell–cell adhesion. Incardiac muscle,Cadherin-2 is an integral component inadherens junctionsresiding atintercalated discs,which function to mechanically and electrically couple adjacentcardiomyocytes.Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including humandilated cardiomyopathy.Variants inCDH2have also been identified to cause a syndromicneurodevelopmental disorder.[8]

Structure

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Cadherin-2 is aproteinwith molecular weight of 99.7 kDa, and 906amino acidsin length.[9]Cadherin-2, a classicalcadherinfrom the cadherin superfamily, is composed of five extracellularcadherin repeats,atransmembrane regionand a highly conservedcytoplasmictail. Cadherin-2, as well as other cadherins,interactwith Cadherin-2 on an adjacent cell in ananti-parallel conformation,thus creating a linear, adhesive "zipper" between cells.[10]

Function

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Cadherin-2, originally named Neural cadherin for its role inneural tissue,plays a role inneuronsand later was found to also play a role incardiac muscleand in cancermetastasis.Cadherin-2 is atransmembrane,homophilicglycoproteinbelonging to thecalcium-dependent cell adhesion molecule family.These proteins haveextracellular domainsthat mediate homophilic interactions between adjacent cells, andC-terminal,cytoplasmictails that mediate binding tocatenins,which in turn interact with theactincytoskeleton.[11][12][13]

Role in development

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Cadherin-2 plays a role in development as a calcium dependent cell–cell adhesionglycoproteinthat functions duringgastrulationand is required for establishment ofleft-right asymmetry.[14]

Cadherin-2 is widely expressed in theembryopost-implantation,showing high levels in themesodermwith sustained expression through adulthood.[15]Cadherin-2 mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociatedmyocytesand abnormal heart tube development occur.[16]Cadherin-2 plays a role in the development of the vertebrate heart at the transition ofepithelial cellstotrabecularand compactmyocardialcell layer formation.[17]An additional study showed thatmyocytesexpressing a dominant negative Cadherin-2 mutant showed significant abnormalities inmyocytedistribution and migration towards theendocardium,resulting in defects in trabecular formation within themyocardium.[18][19]

Role in cardiac muscle

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Incardiac muscle,Cadherin-2 is found atintercalated discstructures which provide end-on cell–cell connections that facilitate mechanical and electrical coupling between adjacentcardiomyocytes.Withinintercalated discsare three types of junctions:adherens junctions,desmosomesandgap junctions;[20]Cadherin-2 is an essential component inadherens junctions,which enables cell–cell adhesion and force transmission across thesarcolemma.[21]Cadherin-2 complexed tocateninshas been described as a master regulator ofintercalated discfunction.[22]Cadherin-2 appears at cell–cell junctions prior togap junctionformation,[23][24]and is critical for normalmyofibrillogenesis.[25]Expression of a mutant form of Cadherin-2 harboring a large deletion in theextracellular domaininhibited the function of endogenous Cadherin-2 in adultventricularcardiomyocytes,and neighboring cardiomyocytes lost cell–cell contact andgap junctionplaques as well.[26]

Mouse models employing transgenesis have highlighted the function of N-cadherin incardiac muscle.Mice with altered expression of N-cadherin and/or E-cadherin showed adilated cardiomyopathyphenotype, likely due to malfunction ofintercalated discs.[27]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 ofintercalated discs,dilated cardiomyopathy,impaired cardiac function, decreasedsarcomerelength, increasedZ-linethickness, decreases inconnexin 43,and a loss in muscular tension. Mice died within two months of transgene expression, mainly due to spontaneousVentricular tachycardia.[28]Further analysis of N-cadherin knockout mice revealed that thearrhythmiaswere likely due toion channelremodeling and aberrant Kv1.5 channel function. These animals showed a prolongedaction potentialduration, reduced density ofinward rectifier potassium channeland decreased expression ofKv1.5,KCNE2andcortactincombined with disruptedactincytoskeletonat thesarcolemma.[29]

Role in neurons

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In neural cells, at certain central nervous systemsynapses,presynaptic to postsynapticadhesionis mediated at least in part by Cadherin-2.[30]N-cadherins interact with catenins to play an important role in learning and memory (For full article seeCadherin-catenin complex in learning and memory). Loss of N-cadherin is also associated with attention-deficit hyperactivity disorder in humans, and impaired synaptic functioning.[31]

Role in cancer metastasis

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Cadherin-2 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 thesrc kinasepathway, which phosphorylatesbeta-cateninsattached to both Cadherin-2 (this protein) andE-cadherins.This causes the intercellular connection between two adjacent endothelial cells to fail and allows the cancer cell to slip through.[32]

Clinical significance

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Variants inCDH2have been identified to cause a syndromicneurodevelopmental disordercharacterized byCorpus callosum,axon, cardiac, ocular, and genital differences.[8]

One study investigating genetic underpinnings ofobsessive-compulsive disorderandTourette disorderfound that whileCDH2variants 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.[33]Further studies in larger cohorts will be required to unequivocally determine this.

In humandilated cardiomyopathy,it was shown that Cadherin-2 expression was enhanced and arranged in a disarrayed fashion, suggesting that disorganization of Cadherin-2 protein inheart diseasemay be a component of remodeling.[34]

Interactions

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Cadherin-2 has been shown tointeractwith:

See also

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References

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  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000024304–Ensembl,May 2017
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  5. ^"UniProt".uniprot.org.Retrieved26 August2022.
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  9. ^"Protein sequence of human CDH2 (Uniprot ID: P19022)".Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).Archived fromthe originalon 24 September 2015.Retrieved20 July2015.
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Further reading

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This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

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