Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Cadherins are a class of type-1 transmembrane proteins. They are dependent 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 a large number of adaptor and signaling proteins, collectively referred to as the cadherin adhesome.
The cadherin superfamily includes cadherins, protocadherins, desmogleins, and desmocollins, and more. In structure, they share cadherin repeats, which are the extracellular Ca2+-binding domains. There are multiple classes of cadherin molecule, each designated with a prefix (in general, noting the type of tissue with which it is associated). It has been observed that cells containing a specific cadherin subtype tend to cluster together to the exclusion of other types, both in cell culture and during development. For example, cells containing N-cadherin tend to cluster with other N-cadherin-expressing cells. However, it has been noted that the mixing speed in the cell culture experiments can have an effect on the extent of homotypic specificity. In addition, several groups have observed heterotypic binding affinity (i.e., binding of different types of cadherin together) in various assays. One current model proposes that cells distinguish cadherin subtypes based on kinetic specificity rather than thermodynamic specificity, as different types of cadherin homotypic bonds have different lifetimes.
Structure and function
Cadherins are synthesized as polypeptides and undergo many post-translational modifications to become the proteins which mediate cell-cell adhesion and recognition. These polypeptides are approximately 720–750 amino acids long. Each cadherin has a small 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. Because cadherins are Ca²⁺ dependent, they have five tandem extracellular domain repeats that act as the binding site for Ca²⁺ ions. Their extracellular domain interacts in two separate trans dimer conformations: strand-swap dimers (S-dimers) and X-dimers. To date, over 100 types of cadherins in humans have been identified and sequenced.
The functionality of cadherins relies upon the formation of two identical subunits, known as homodimers. 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. 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 actin cytoskeleton portion of the cadherin.
Cadherins behave as both receptors and ligands for other molecules. During development, their behavior assists in properly positioning cells: they are responsible for the separation of the different tissue layers, and for cellular migration. In the very early stages of development, E-cadherin (epithelial cadherin) is most greatly expressed. Many cadherins are specified for specific functions in the cell, and they are differentially expressed in a developing embryo. For example, during neurulation, when the neural plate is forming in the embryo, the tissues residing near the cranial neural folds have decreased N-cadherin expression. Conversely, the expression of the N-cadherins remains unchanged in the other regions of the neural tube that is located on the anterior-posterior axis of the vertebrate. The expression of the different types of cadherins in the cell are varying dependent upon the specific differentiation and specification of the organism during development.
Cadherins play a vital role in the migration of cells through the epithelial-mesenchymal transition (EMT), which requires cadherins to forms adherents junctions with neighboring cells. In neural crest cells, which are transient cells that arise in the developing organism during gastrulation and function in the patterning of the vertebrate body plan, the catherine are necessary to allow migration of cells to form tissues or organs. In addition, cadherins responsible in the EMT event in early development have also been shown to be critical in the reprogramming of specified adult cells into a pluripotent state, forming induced pluripotent stem cells (iPSC's).
After development, cadherins play a role in maintaining cell and tissue structure, and in cellular movement. Regulation of cadherin expression can occur through promoter methylation among other epigenetic mechanisms.
The E-cadherin–catenin complex plays a key role in cellular adhesion; loss of this function has been associated with greater tumour metastasis.
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. This large amount of diversity is accomplished by having multiple cadherin encoding genes combined with alternative RNA splicing mechanisms. Invertebrates contain fewer than 20 types of cadherins.
Different members of the cadherin family are found in different locations.
- CDH1 - E-cadherin (epithelial): E-cadherins are found in epithelial tissue
- 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.
PCDH15; PCDH17; PCDH18; PCDH19; PCDH20; PCDH7; PCDH8; PCDH9; PCDHA1; PCDHA10; PCDHA11; PCDHA12; PCDHA13; PCDHA2; PCDHA3; PCDHA4; PCDHA5; PCDHA6; PCDHA7; PCDHA8; PCDHA9; PCDHAC1; PCDHAC2; PCDHB1; PCDHB10; PCDHB11; PCDHB12; PCDHB13; PCDHB14; PCDHB15; PCDHB16; PCDHB17; PCDHB18; PCDHB2; PCDHB3; PCDHB4; PCDHB5; PCDHB6; PCDHB7; PCDHB8; PCDHB9; PCDHGA1; PCDHGA10; PCDHGA11; PCDHGA12; PCDHGA2; PCDHGA3; PCDHGA4; PCDHGA5; PCDHGA6; PCDHGA7; PCDHGA8; PCDHGA9; PCDHGB1; PCDHGB2; PCDHGB3; PCDHGB4; PCDHGB5; PCDHGB6; PCDHGB7; PCDHGC3; PCDHGC4; PCDHGC5
- CDH9 - cadherin 9, type 2 (T1-cadherin)
- CDH10 - cadherin 10, type 2 (T2-cadherin)
- CDH4 - R-cadherin (retinal)
- CDH5 - VE-cadherin (vascular endothelial)
- CDH6 - K-cadherin (kidney)
- CDH7 - cadherin 7, type 2
- CDH8 - cadherin 8, type 2
- CDH11 - OB-cadherin (osteoblast)
- CDH13 - T-cadherin - H-cadherin (heart)
- CDH15 - M-cadherin (myotubule)
- CDH16 - KSP-cadherin
- CDH17 - LI cadherin (liver-intestine)
- CDH18 - cadherin 18, type 2
- CDH19 - cadherin 19, type 2
- CDH20 - cadherin 20, type 2
- CDH23 - cadherin 23 (neurosensory epithelium)
- CDH10; CDH11; CDH13; CDH15; CDH16; CDH17;
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