Cadherin

Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other.^[1] Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca²⁺) ions to function, hence their name. Cell-cell adhesion is mediated by extracellular cadherin domains, whereas the intracellular cytoplasmic tail associates with numerous adaptors and signaling proteins, collectively referred to as the cadherin adhesome.

Background

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The cadherin family is essential in maintaining cell-cell contact and regulating cytoskeletal complexes. The cadherin superfamily includes cadherins,

The intracellular portion of classical cadherins interacts with a complex of proteins that allows connection to the actin cytoskeleton. Although classical cadherins take a role in cell layer formation and structure formation, desmosomal cadherins focus on resisting cell damage. Desmosomal cadherins maintain the function of desmosomes that is to overturn the mechanical stress of the tissues. Similar to classical cadherins, desmosomal cadherins have a single transmembrane domain, five EC repeats, and an intracellular domain. There are two types of desmosomal cadherins: desmogleins and desmocollins. These contain an intracellular anchor and cadherin like sequence (ICS). The adaptor proteins that associate with desmosomal cadherins are plakoglobin (related to ${\displaystyle \beta }$-catenin), plakophilins (p120 catenin subfamily), and desmoplakins. The major function of desmoplakins is to bind to intermediate filament by interacting with plakoglobin, which attach to the ICS of desmogleins, desmocollins and plakophilins.

Cells containing a specific cadherin subtype tend to cluster together to the exclusion of other types, both in cell culture and during

Cadherins are synthesized as polypeptides and undergo many post-translational modifications to become the proteins which mediate cell-cell adhesion and recognition.^[11] These polypeptides are approximately 720–750 amino acids long. Each cadherin has a small C-terminal cytoplasmic component, a transmembrane component, and the remaining bulk of the protein is extra-cellular (outside the cell). The transmembrane component consists of single chain glycoprotein repeats.^[12]  Because cadherins are Ca²⁺ dependent, they have five tandem extracellular domain repeats that act as the binding site for Ca²⁺ ions.^[13]  Their extracellular domain interacts with two separate trans dimer conformations: strand-swap dimers (S-dimers) and X-dimers.^[13] To date, over 100 types of cadherins in humans have been identified and sequenced.^[14]

 The functionality of cadherins relies upon the formation of two identical subunits, known as homodimers.^[12] The homodimeric cadherins create cell-cell adhesion with cadherins present in the membranes of other cells through changing conformation from cis-dimers to trans-dimers.^[12] Once the cell-cell adhesion between cadherins present in the cell membranes of two different cells has formed, adherens junctions can then be made when protein complexes, usually composed of α-, β-, and γ-catenins, bind to the cytoplasmic portion of the cadherin.^[12] Regulatory proteins include p-120 catenin, ${\displaystyle \alpha }$-catenin,  ${\displaystyle \beta }$-catenin, and vinculin. Binding of p-120 catenin and ${\displaystyle \beta }$-catenin to the homodimer increases the stability of the classical cadherin. ${\displaystyle \alpha }$-catenin is engaged by p120-catenin complex, where vinculin is recruited to take a role in indirect association with actin cytoskeleton.^[4] However, cadherin-catenin complex can also bind directly to the actin without the help of vinculin. Moreover, the strength of cadherin adhesion can increase by dephosphorylation of p120 catenin and the binding of ${\displaystyle \alpha }$-catenin and vinculin.

Function

Development

Cadherins behave as both receptors and ligands for other molecules. During development, their behavior assists at properly positioning cells: they are responsible for the separation of the different tissue layers and for cellular migration.

After development, cadherins play a role in maintaining cell and tissue structure, and in cellular movement.[14] Regulation of cadherin expression can occur through promoter methylation among other epigenetic mechanisms.^[18]

Tumour metastasis

The E-cadherin–catenin complex plays a key role in cellular adhesion; loss of this function has been associated with increased invasiveness and metastasis of tumors.^[19] The suppression of E-cadherin expression is regarded as one of the main molecular events responsible for dysfunction in cell-cell adhesion, which can lead to local invasion and ultimately tumor development. Because E-cadherins play an important role in tumor suppression, they are also referred to as the "suppressors of invasion".^[20]

Additionally, the overexpression of type 5, 6, and 17 cadherins alone or in combination can lead to cancer metastasis, and ongoing research aims to block their ability to function as ligands for integral membrane proteins.^[21]

Correlation to cancer

It has been discovered that cadherins and other additional factors are correlated to the formation and growth of some cancers and how a tumor continues to grow. The E-cadherins, known as the epithelial cadherins, are on the surface of one cell and can bind with those of the same kind on another to form bridges.^[22] The loss of the cell adhesion molecules, E cadherins, is causally involved in the formation of epithelial types of cancers such as carcinomas. The changes in any types of cadherin expression may not only control tumor cell adhesion but also may affect signal transduction leading to the cancer cells growing uncontrollably.^[23]

In epithelial cell cancers, disrupted cell to cell adhesion might lead to the development of secondary malignant growths; they are distant from the primary site of cancer and can result from the abnormalities in the expression of E-cadherins or its associated

This family of glycoproteins is responsible for calcium-dependent mechanism of intracellular adhesion. E-cadherins are crucial in embryogenesis during several processes, including gastrulation, neurulation, and organogenesis. Furthermore, suppression of E-cadherins impairs intracellular adhesion. The levels of these molecules increase during the luteal phase while their expression is regulated by progesterone with endometrial calcitonin.[24]

Types

There are said to be over 100 different types of cadherins found in vertebrates, which can be classified into four groups: classical, desmosomal, protocadherins, and unconventional.^[26][27] These large amount of diversities are accomplished by having multiple cadherin encoding genes combined with alternative RNA splicing mechanisms. Invertebrates contain fewer than 20 types of cadherins.^[27]

Classical

Different members of the cadherin family are found in different locations.

• CDH1 – E-cadherin (epithelial): E-cadherins are found in epithelial tissue; not to be confused with the APC/C activator protein CDH1. E-cadherins play a vital role in cancer formation, as deregulation of E-cadherin functions is a crucial step in the formation of breast cancer tumors.^[28]
• CDH2
  – N-cadherin (neural): N-cadherins are found in neurons
• CDH12 – cadherin 12, type 2 (N-cadherin 2)
• CDH3 – P-cadherin (placental): P-cadherins are found in the placenta.

Desmosomal

• DSG4
  )
• Desmocollin (DSC1, DSC2, DSC3)

Protocadherins

Protocadherins are the largest mammalian subgroup of the cadherin superfamily of homophilic cell-adhesion proteins.

Unconventional/ungrouped

See also

• Masatoshi Takeichi
• Catenin
• List of target antigens in pemphigus

References