# Cadherin-2

Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 (cluster of differentiation 325). Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.

## Structure

Cadherin-2 is a protein with molecular weight of 99.7 kDa, and 906 amino acids in length. Cadherin-2, a classical cadherin from the cadherin superfamily, is composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Cadherin-2, as well as other cadherins, interact with Cadherin-2 on an adjacent cell in an anti-parallel conformation, thus creating a linear, adhesive "zipper" between cells.

## Function

Cadherin-2, originally named Neural cadherin 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. Cadherin-2 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.

### Role in development

Cadherin-2 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.
Cadherin-2 is widely expressed in the embryo post-implantation, showing high levels in the mesoderm with sustained expression through adulthood. Cadherin-2 mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociated myocytes and abnormal heart tube development occur. Cadherin-2 plays a role in the development of the vertebrate heart at the transition of epithelial cells to trabecular and compact myocardial cell layer formation. An additional study showed that myocytes expressing a dominant negative Cadherin-2 mutant showed significant abnormalities in myocyte distribution and migration towards the endocardium, resulting in defects in trabecular formation within the myocardium.

### Role in cardiac muscle

In cardiac muscle, Cadherin-2 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; Cadherin-2 is an essential component in adherens junctions, which enables cell–cell adhesion and force transmission across the sarcolemma. Cadherin-2 complexed to catenins has been described as a master regulator of intercalated disc function. Cadherin-2 appears at cell–cell junctions prior to gap junction formation, and is critical for normal myofibrillogenesis. Expression of a mutant form of Cadherin-2 harboring a large deletion in the extracellular domain inhibited the function of endogenous Cadherin-2 in adult ventricular cardiomyocytes, and neighboring cardiomyocytes lost cell–cell contact and gap junction plaques as well.
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. 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. 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.

### Role in neurons

In neural cells, at certain central nervous system synapses, presynaptic to postsynaptic adhesion is mediated at least in part by Cadherin-2. 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). Loss of N-cadherin is also associated with attention-deficit hyperactivity disorder in humans, and impaired synaptic functioning.

### Role in cancer metastasis

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 the src kinase pathway, which phosphorylates beta-catenins attached to both Cadherin-2 (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.

## Clinical significance

Variants in CDH2 have been identified to cause a syndromic neurodevelopmental disorder characterized by Corpus callosum, axon, cardiac, ocular, and genital differences.
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. Further studies in larger cohorts will be required to unequivocally determine this.
In human dilated cardiomyopathy, it was shown that Cadherin-2 expression was enhanced and arranged in a disarrayed fashion, suggesting that disorganization of Cadherin-2 protein in heart disease may be a component of remodeling.

## Interactions

Cadherin-2 has been shown to interact with:
* Beta-catenin,
* CDH11,
* type IIb RPTPs including PTPmu (CTNND1),
* CTNNA1,
* LRRC7,
* PTPRM)
* PTPrho (PTPRT), and
* Plakoglobin.
* XIRP1
* SCARB2