CDH2

Official Full Name

cadherin 2

Organism

Homo sapiens

GeneID

1000

Background

This gene encodes a classical cadherin and member of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein is proteolytically processed to generate a calcium-dependent cell adhesion molecule and glycoprotein. This protein plays a role in the establishment of left-right asymmetry, development of the nervous system and the formation of cartilage and bone. [provided by RefSeq, Nov 2015]

Synonyms

CDHN; NCAD; ACOGS; ADHD8; CD325; ARVD14; CDw325;

Bio Chemical Class

Cadherin protein

Protein Sequence

MCRIAGALRTLLPLLAALLQASVEASGEIALCKTGFPEDVYSAVLSKDVHEGQPLLNVKFSNCNGKRKVQYESSEPADFKVDEDGMVYAVRSFPLSSEHAKFLIYAQDKETQEKWQVAVKLSLKPTLTEESVKESAEVEEIVFPRQFSKHSGHLQRQKRDWVIPPINLPENSRGPFPQELVRIRSDRDKNLSLRYSVTGPGADQPPTGIFIINPISGQLSVTKPLDREQIARFHLRAHAVDINGNQVENPIDIVINVIDMNDNRPEFLHQVWNGTVPEGSKPGTYVMTVTAIDADDPNALNGMLRYRIVSQAPSTPSPNMFTINNETGDIITVAAGLDREKVQQYTLIIQATDMEGNPTYGLSNTATAVITVTDVNDNPPEFTAMTFYGEVPENRVDIIVANLTVTDKDQPHTPAWNAVYRISGGDPTGRFAIQTDPNSNDGLVTVVKPIDFETNRMFVLTVAAENQVPLAKGIQHPPQSTATVSVTVIDVNENPYFAPNPKIIRQEEGLHAGTMLTTFTAQDPDRYMQQNIRYTKLSDPANWLKIDPVNGQITTIAVLDRESPNVKNNIYNATFLASDNGIPPMSGTGTLQIYLLDINDNAPQVLPQEAETCETPDPNSINITALDYDIDPNAGPFAFDLPLSPVTIKRNWTITRLNGDFAQLNLKIKFLEAGIYEVPIIITDSGNPPKSNISILRVKVCQCDSNGDCTDVDRIVGAGLGTGAIIAILLCIIILLILVLMFVVWMKRRDKERQAKQLLIDPEDDVRDNILKYDEEGGGEEDQDYDLSQLQQPDTVEPDAIKPVGIRRMDERPIHAEPQYPVRSAAPHPGDIGDFINEGLKAADNDPTAPPYDSLLVFDYEGSGSTAGSLSSLNSSSSGGEQDYDYLNDWGPRFKKLADMYGGGDD

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The CDH2 gene encodes N-cadherin, a classical cadherin protein belonging to the cadherin superfamily. Found on chromosome 18q12.1, this gene has 16 exons and spans around 250 Kb. Crucially facilitating homotypic cell-cell adhesion, N-cadherin is a calcium-dependent cell adhesion protein. Five external domains, a transmembrane region, and an intracellular domain define its structural characterization from a preproprotein into a functioning glycoprotein. Left-right asymmetry, embryonic development, brain system construction, and skeletal development all depend on this protein in great measure.

Molecular Mechanisms of CDH2

N-cadherin contributes to tissue integrity and cellular organization by dimerizing with its counterpart on nearby cells, hence mediating cell adhesion. By attaching neural stem cells to ependymocytes in the subependymal zone, CDH2 functions as a fundamental regulator in these cells. This anchoring is disturbed when broken by matrix metalloproteinase 24 (MMP24), therefore influencing neural stem cell quiescence and encouraging proliferation. Additionally, CDH2 is essential for the formation of cell-to-cell junctions in pancreatic beta cells and neural crest stem (NCS) cells, facilitating neurite branching and synaptic organization.

CDH2 adversely controls migration starting and speed in Drosophila glial cells. By interactions with the ARP2/3 complex, excessive expression of N-cadherin lowers migratory efficiency and acts to limit actin assembly. Reduced CDH2 expression, on the other hand, raises α-catenin membrane levels, therefore improving actin branching and motility.

In neurons, CDH2 also controls synaptic vesicle exocytosis and endocytosis, hence preserving structural stability during high-frequency vesicle fusion. Knockout models show how N-cadherin expression improves synaptic vesicle recycling. This ability emphasizes the important part N-cadherin performs in maintaining neuronal activity.

Post-Translational Modifications of N-Cadherin

N-glycosylation is essential for N-cadherin functioning among other post-translational modifications. N-cadherin is shown in canine kidney cell lines to undergo N-glycosylation mediated by glycosyltransferases including N-acetylglucosamine transferase V (GnT-V), which catalyzes the addition of β(1,6)-linked N-acetylglucosamine. Reducing N-glycosylation alters N-cadherin stability, localization, and cell adhesion. Three main glycosylation sites—asn207, asn325, and asn402—with abnormal glycosylation linked with cancer growth and metastasis are found.

In glioblastoma, N-glycosylation at Asn402 especially controls N-cadherin stability and migration. Reducing this glycosylation causes N-cadherin to undergo proteasomal breakdown, therefore compromising glioblastoma cell motility without changing mRNA transcript levels. This implies that glioblastoma pathogenesis depends critically on N-cadherin.

Figure 1 illustrates how N-cadherin promotes tumor metastasis through various molecular pathways and mechanisms, facilitating tumor cell migration and invasion. Figure 1. N-cadherin promotes tumor metastasis through multiple pathways.

CDH2 in Reproductive Biology

In Sertoli cells found in the testis, CDH2 expression is notable and forms cell connections necessary for sustaining the blood-testis barrier (BTB) and promoting spermatogenesis. Severe testicular abnormalities include diminished germ cell populations and altered BTB function shown by CDH2-knockout experiments cause delayed meiosis and increased death of germ cells. By thus stabilizing BTB structure and function, CDH2 guarantees proper spermatogenesis.

CDH2 in Disease Pathogenesis

N-cadherin expression is frequently upregulated during epithelial-to-mesenchymal transition (EMT), a hallmark of cancer metastasis. Reduced E-cadherin and increased N-cadherin expression define this "cadherin switch," which increases cell invasiveness and migration and correlates with poor patient outcomes in malignancies like breast cancer and cholangiocarcinoma. N-cadherin interacts with fibroblast growth factor receptor (FGFR) in breast cancer to activate the MEK/MAPK signaling pathway and induce matrix metalloproteinase-9 (MMP-9) production, hence fostering tumor invasion.

Several neurological disorders, including neurodevelopmental syndromes and Attention Deficit-Hyperactivity Disorder (ADHD), have CDH2-linked involvement. It helps to maintain synaptic integrity and dendritic spine density; its malfunction might influence brain network connection, therefore producing cognitive and behavioral disorders.

Maintaining cardiomyocyte adhesion and vascular endothelial integrity calls upon N-cadherin. Dysregulation or mutations in CDH2 expression might throw off cardiac tissue organization, aggravating disorders like heart failure and arrhythmias.

Therapeutic Implications

In cancer and regenerative medicine, CDH2 shows a potential therapeutic target given its many functions in cell adhesion, migration, and signaling. New approaches for treating metastatic tumors might come from strategies meant to control CDH2 expression or post-translational alterations, including N-glycosylation inhibitors. Approaches to improve CDH2-mediated cell adhesion might also help tissue engineering and brain repair.

References:

Parker J, Hockney S, Blaschuk OW, et al. Targeting N-cadherin (CDH2) and the malignant bone marrow microenvironment in acute leukaemia. Expert Rev Mol Med. 2023 May 3;25:e16.
Issagholian L, Tabaie E, Reddy AJ, et al. Expression of E-cadherin and N-cadherin in Epithelial-to-Mesenchymal Transition of Osteosarcoma: A Systematic Review. Cureus. 2023 Nov 27;15(11):e49521.

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