CDH1 - cadherin 1 |Elisa - Clia - Antibody - Protein

Background

Cadherin 1 (CDH1), also known as E-cadherin (epithelial cadherin), is a transmembrane glycoprotein primarily responsible for cell-cell adhesion in epithelial tissues. It is a crucial member of the cadherin superfamily, a group of calcium-dependent adhesion molecules that mediate homophilic binding interactions between cells. CDH1 is indispensable for maintaining cellular architecture and tissue integrity, especially within epithelial layers, where it anchors cells to each other, forming adherens junctions that maintain cellular polarity and tissue structure. CDH1 also plays a significant role in regulating signaling pathways involved in cell differentiation, proliferation, and survival.

The biological significance of CDH1 extends to tumor suppression, as its presence prevents detachment of cells from the epithelial layer, which could otherwise lead to metastasis. Loss or downregulation of CDH1 is frequently observed in various cancers, particularly in those characterized by epithelial-mesenchymal transition (EMT), a process by which epithelial cells acquire migratory and invasive properties. Therefore, CDH1 is not only integral to tissue integrity but also to preventing disease progression, especially in oncogenesis.

Protein Structure

The CDH1 protein is a type I transmembrane glycoprotein that contains several distinct structural regions:

Extracellular Domain:

• The extracellular domain of CDH1 consists of five tandem cadherin repeats (EC1 to EC5), each of which can bind calcium ions. These repeats provide the structural stability needed for cell-cell adhesion, as calcium ions prevent cadherin from undergoing conformational changes that could compromise its adhesive function.
• The EC1 domain is responsible for homophilic binding (i.e., binding to another E-cadherin molecule on an adjacent cell) through a "strand-swapping" mechanism, in which a tryptophan residue from one CDH1 molecule fits into a hydrophobic pocket on the adjacent CDH1 molecule. This interaction establishes a strong, calcium-dependent bond that underpins the adhesive properties of CDH1.
• The remaining cadherin repeats (EC2-EC5) stabilize this interaction and provide additional contact points to reinforce cell-cell adhesion.

Transmembrane Domain:

• The single transmembrane domain of CDH1 anchors it within the cell membrane, providing a physical link between the extracellular cadherin repeats and the intracellular cytoplasmic tail. This region is essential for maintaining the protein's localization at the cell membrane and enabling its role in signal transduction.

Cytoplasmic Domain:

• The cytoplasmic tail of CDH1 interacts with catenin proteins, including β-catenin, p120-catenin, and α-catenin, which link CDH1 to the actin cytoskeleton. β-catenin binds directly to the cytoplasmic domain of CDH1, while α-catenin interacts with β-catenin to anchor the complex to actin filaments.
• This structural arrangement facilitates strong cell-cell adhesion, maintaining tissue integrity and cellular polarity. Additionally, these catenin interactions are critical for transducing intracellular signals that influence cell behavior, such as cell proliferation and migration.

Calcium-Binding Sites:

• Calcium ions bind between the extracellular cadherin repeats, stabilizing the protein’s structure. The calcium-binding sites prevent CDH1 from becoming flexible and thus non-adhesive, ensuring the rigidity required for stable cell-cell adhesion.

Classification and Subtypes

CDH1 belongs to the classical cadherins subgroup within the larger cadherin superfamily. Classical cadherins are generally characterized by five extracellular cadherin repeats and a conserved cytoplasmic domain that interacts with catenins. CDH1 specifically falls under type I cadherins, known for their essential role in forming adherens junctions in epithelial cells. While CDH1 (E-cadherin) is primarily found in epithelial tissues, other classical cadherins, such as N-cadherin (CDH2) and P-cadherin (CDH3), are expressed in neuronal and placental tissues, respectively, highlighting a degree of tissue specificity among cadherins.

Function and Biological Significance

The primary function of CDH1 is mediating cell-cell adhesion in epithelial tissues, forming the basis of adherens junctions that maintain tissue architecture and cellular polarity. Its functions and significance are outlined below:

Cell Adhesion and Tissue Integrity:

• CDH1 enables epithelial cells to adhere tightly to each other through homophilic interactions. This adhesion is essential for forming cohesive tissue structures, such as those found in epithelial linings. The linkage of CDH1 to the actin cytoskeleton via catenins reinforces this adhesion, providing mechanical strength to the tissue.

Cell Polarity and Differentiation:

• CDH1 plays a pivotal role in maintaining apical-basal polarity in epithelial cells, ensuring that cells organize with a defined orientation, which is necessary for tissue function. This polarity enables cells to differentiate and organize properly within tissues, influencing the direction of cell growth and functional specialization.

Signal Transduction and Gene Regulation:

• Through its interaction with catenins, especially β-catenin, CDH1 participates in the regulation of several signaling pathways. In a complex with CDH1, β-catenin is sequestered at the membrane and unable to activate gene transcription. However, when CDH1 expression is lost or reduced, β-catenin can translocate to the nucleus and promote the transcription of genes associated with cell proliferation and EMT, contributing to oncogenesis.

Tumor Suppression and EMT Inhibition:

• CDH1 is regarded as a tumor suppressor due to its ability to prevent EMT, a process by which epithelial cells lose their polarity and adhesion to acquire migratory and invasive properties. CDH1 downregulation is frequently observed in metastatic cancers and is associated with poor prognosis. Loss of CDH1 function allows cells to detach from primary tumor sites, invade surrounding tissues, and spread to distant organs.

Clinical Issues

Mutations or downregulation of CDH1 are implicated in various diseases, most notably cancer. Clinical issues associated with CDH1 include:

Hereditary Diffuse Gastric Cancer (HDGC):

• Germline mutations in the CDH1 gene are linked to HDGC, an inherited cancer syndrome. Individuals with these mutations have a significantly increased risk of developing diffuse-type gastric cancer, characterized by scattered cancer cells that infiltrate the stomach wall, as well as lobular breast cancer in women. CDH1 mutations are therefore considered a genetic marker for HDGC, and prophylactic gastrectomy is often recommended for individuals with high-risk mutations.

Cancer Metastasis:

• CDH1 downregulation or loss is common in many cancers, including breast, colorectal, prostate, and ovarian cancers. In these cancers, the reduction in CDH1 expression promotes EMT, allowing cancer cells to invade other tissues and metastasize. CDH1 expression levels are often used as a prognostic indicator, as low levels correlate with increased tumor aggressiveness and poorer clinical outcomes.

Inflammatory Diseases:

• Alterations in CDH1 expression have been observed in inflammatory diseases, such as inflammatory bowel disease (IBD). In such conditions, decreased CDH1 expression compromises the epithelial barrier, allowing immune cells and pathogens to infiltrate the tissue and exacerbate inflammation.

Congenital Abnormalities:

• CDH1 mutations may be associated with developmental abnormalities, particularly in tissues that require strong cell-cell adhesion for proper morphogenesis, such as craniofacial structures. Although rare, congenital mutations in CDH1 can lead to malformations in tissues where epithelial integrity is crucial.

Summary

CDH1 (E-cadherin) is a calcium-dependent cell adhesion protein essential for maintaining cell-cell adhesion, tissue integrity, and cellular polarity in epithelial tissues. Structurally, CDH1 consists of five extracellular cadherin repeats that bind calcium ions, a transmembrane domain, and a cytoplasmic domain that interacts with catenins, linking it to the actin cytoskeleton. Through homophilic interactions, CDH1 forms adherens junctions that stabilize tissue architecture and support epithelial polarity. Its functions extend to regulating gene transcription by sequestering β-catenin at the cell membrane, preventing pro-tumorigenic signaling.

Clinically, CDH1 is a key tumor suppressor, and its downregulation is associated with EMT and metastasis in several cancers, including breast and gastric cancers. Mutations in the CDH1 gene are implicated in hereditary diffuse gastric cancer and lobular breast cancer, prompting genetic screening and preventive measures in high-risk individuals. Loss of CDH1 function is a hallmark of aggressive cancers and a prognostic indicator in oncology. Additionally, CDH1 dysfunction is associated with inflammatory diseases and developmental abnormalities. The critical role of CDH1 in cell adhesion and tumor suppression underscores its importance in maintaining epithelial integrity and preventing oncogenic progression, making it a significant target in cancer diagnostics and therapeutics.