CDH2 - cadherin 2 |Elisa - Clia - Antibody - Protein

Background

Cadherin 2 (CDH2), also known as N-cadherin (neural cadherin), is a calcium-dependent cell adhesion molecule that belongs to the classical cadherin family. This protein is primarily expressed in neural tissue, muscle, and endothelial cells, facilitating cell-cell adhesion that is crucial for the organization and stability of various tissues, particularly during development. CDH2 mediates homophilic cell adhesion by binding to other N-cadherin molecules on neighboring cells, helping establish stable cellular contacts necessary for tissue integrity and function. Unlike CDH1, which is primarily expressed in epithelial cells, CDH2 is prevalent in mesenchymal and neural cell types and is integral to processes like embryogenesis, neural development, and wound healing.

N-cadherin’s role extends beyond basic cell adhesion, as it is actively involved in signaling pathways that regulate cell migration, differentiation, and survival. In particular, CDH2 is essential during the development of the nervous system, heart, and vasculature, contributing to the morphogenesis of organs and the maintenance of neuronal connections. Additionally, CDH2 expression has significant implications in cancer progression and metastasis, particularly through the process of epithelial-mesenchymal transition (EMT), where it replaces CDH1 as cells transition to a more migratory, invasive phenotype. This behavior makes CDH2 a critical molecule not only in normal development but also in disease progression.

Protein Structure

CDH2 is a type I transmembrane glycoprotein that consists of three main structural domains:

Extracellular Domain:

• The extracellular region of CDH2 is composed of five cadherin repeats (EC1 to EC5), each capable of binding calcium ions. These repeats allow CDH2 to mediate cell-cell adhesion through a homophilic binding mechanism, primarily involving interactions between the EC1 domains of opposing N-cadherin molecules.
• The binding interaction in the EC1 domain occurs through a “strand-swapping” mechanism, in which a conserved tryptophan residue (W2) from one CDH2 molecule inserts into a hydrophobic pocket on the neighboring CDH2 molecule. This interaction forms a robust, calcium-dependent adhesive contact critical for cell-cell adhesion.
• The calcium-binding sites are located between the cadherin repeats, stabilizing the structure and preventing conformational changes that would otherwise impair the adhesive function. Calcium ions provide rigidity to the extracellular domain, ensuring that CDH2 maintains its adhesion capabilities under varying physiological conditions.

Transmembrane Domain:

• The single-pass transmembrane domain anchors CDH2 within the cell membrane, connecting the extracellular cadherin repeats to the intracellular region. This hydrophobic region is responsible for stabilizing CDH2’s positioning within the membrane and is essential for mediating interactions between extracellular and intracellular environments.

Cytoplasmic Domain:

• The cytoplasmic tail of CDH2 interacts with catenins, including β-catenin, p120-catenin, and α-catenin, which link CDH2 to the actin cytoskeleton. This complex forms a structural linkage that strengthens cell-cell adhesion and allows CDH2 to participate in intracellular signaling.
• β-catenin binds directly to the cytoplasmic tail of CDH2, while α-catenin connects this complex to actin filaments. The association between CDH2 and catenins is dynamic, as it also serves as a platform for signal transduction that regulates cellular behaviors like migration, proliferation, and survival.

Classification and Subtypes

CDH2 belongs to the classical cadherins within the cadherin superfamily, specifically identified as a type I cadherin. Classical cadherins are typically characterized by five extracellular cadherin repeats and a conserved cytoplasmic tail that interacts with catenins. While CDH2 is most closely related to CDH1 (E-cadherin), they are expressed in different tissue types, with CDH2 being dominant in neural, mesenchymal, and endothelial cells. There are no known subtypes of CDH2 itself, but it is often co-expressed with other cadherins depending on the tissue context, such as with vascular endothelial cadherin (VE-cadherin) in endothelial tissues or with R-cadherin in muscle.

Function and Biological Significance

CDH2 performs a range of critical functions:

Cell Adhesion and Tissue Formation:

• CDH2 enables cells to adhere to one another through calcium-dependent homophilic interactions. This adhesive property is fundamental in tissues that undergo dynamic structural changes, such as in the developing nervous system and heart. The presence of CDH2 stabilizes cell layers and is essential for the formation and maintenance of tissue integrity in these environments.

Neuronal Development and Synapse Formation:

• In the nervous system, CDH2 mediates axonal guidance, synapse formation, and the maintenance of neuronal connections. It is actively involved in synaptic plasticity and the stabilization of synaptic contacts, influencing the formation of functional neural circuits.

Regulation of Cell Migration and EMT:

• CDH2 plays a critical role in regulating cell migration, particularly in mesenchymal cells and during wound healing. It facilitates cellular migration through interactions with intracellular signaling pathways that control actin dynamics and cellular movement.
• During EMT, epithelial cells lose CDH1 expression and gain CDH2 expression, enabling them to acquire a more migratory and invasive phenotype. This switch from CDH1 to CDH2 is crucial for processes like embryogenesis and wound repair but also plays a role in cancer metastasis.

Cell Survival and Signal Transduction:

• Through its association with β-catenin, CDH2 influences signaling pathways that regulate cell survival and proliferation. By sequestering β-catenin at the cell membrane, CDH2 can modulate the availability of β-catenin for Wnt signaling, thereby impacting gene expression related to cellular growth and survival.

Clinical Issues

Cancer and Metastasis:

• CDH2 is frequently upregulated in cancers, particularly those undergoing EMT, such as breast, prostate, and lung cancers. Increased CDH2 expression is associated with enhanced metastatic potential, as it facilitates detachment from the primary tumor, invasion into surrounding tissues, and colonization of distant sites.
• In addition, CDH2-mediated signaling pathways that control cell survival and migration are often dysregulated in tumors, promoting cancer progression. CDH2’s role in metastasis makes it a therapeutic target, with ongoing research aiming to inhibit its function to prevent cancer spread.

Cardiovascular Diseases:

• CDH2 is crucial in cardiac development, especially during the formation of the heart’s structural components. Mutations in CDH2 are linked to congenital heart diseases and conditions such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Loss of CDH2 function in cardiomyocytes can impair cell-cell adhesion, leading to heart muscle degeneration and increased susceptibility to arrhythmias.

Neurological Disorders:

• Given CDH2’s importance in the nervous system, alterations in its expression or function can impact neural development and synaptic plasticity. Changes in CDH2 expression have been associated with neurodevelopmental disorders and neurodegenerative diseases. For instance, dysregulated CDH2 function may contribute to impaired neuronal connectivity observed in autism spectrum disorders and certain forms of intellectual disability.

Developmental Abnormalities:

• CDH2’s role in cellular migration and tissue morphogenesis during embryogenesis makes it essential for proper organ formation. Loss of CDH2 function can lead to developmental abnormalities, particularly in structures like the brain, heart, and skeletal system. The protein is indispensable for the structural organization and functional maturation of these tissues.

Summary

CDH2 (N-cadherin) is a calcium-dependent cell adhesion protein that belongs to the classical cadherin family. Structurally, CDH2 consists of five extracellular cadherin repeats that mediate homophilic cell-cell adhesion, a transmembrane domain anchoring it in the cell membrane, and a cytoplasmic tail that interacts with catenins to link CDH2 to the actin cytoskeleton. These structural features enable CDH2 to form stable cell-cell adhesions, which are essential for the integrity and functionality of neural, cardiac, and other tissues during development and in adulthood.

Functionally, CDH2 is crucial for tissue organization, neuronal development, and cell migration. Its role in mediating EMT and promoting a migratory phenotype makes it indispensable during embryogenesis and wound healing, while also linking it to metastatic processes in cancer. Clinical issues related to CDH2 dysfunction include its upregulation in various cancers, leading to increased invasiveness, as well as its association with cardiovascular and neurological diseases. Mutations or dysregulation of CDH2 can disrupt tissue integrity and lead to developmental abnormalities, highlighting its essential role in cellular adhesion and signaling.

CDH2’s significance spans normal developmental processes and disease states, making it a key target for therapeutic intervention in conditions such as cancer metastasis, cardiovascular diseases, and neurodevelopmental disorders.