Cadherin

• OMIM: 192090

• MGI: 88354

Cadherins ( English Adhering of calcium, such as calcium adherine ) are of calcium ions (Ca2 ) -dependent transmembrane glycoproteins from the group of adhesion proteins. They occur in desmosomes and adherens junction and cause cell contacts in different tissues. Cadherins play a role in the stabilization of cell-cell contacts, the embryonic morphogenesis, the maintenance of cell polarity and signal transduction.

With the help of cryo-electron tomography was able to prove that the stabilization is done by thread-like adhesion proteins that protrude from the cell membranes and hook together.

• 2.1 catenins

Structure and subdivision

From the superfamily of cadherins than 300 proteins are currently known only in vertebrates. In humans, up to date, more than 80 cadherins have been identified. Common to all cadherins several extracellular cadherin domains ( ECs). An EC is approximately 100 amino acids long, evolutionarily conserved and has very negatively charged sequence motifs that calcium -ion-dependent, mediate homophilic bonds. Over short, about ten amino acid long linker sequences, these ECs repeat tandemly between 5 - to 34 - times, where the ECs are numbered beginning at the N -terminal end. Based on this number of ECs, but also on the cytoplasmic domain and the size of a cadherin as well as gene clusters, the superfamily of cadherins is divided into seven groups:

The most important and best-studied representatives, are the classic cadherins, such as E- and N- cadherins, and P ( planzetare ) - and VE - cadherin. These play an important role in the malignant progression. They form in the cell parallel cis- dimers. In this conformation, it is capable of forming a trans- dimerization with an identical cadherin dimer in the opposite cell and so bridge the extracellular space between the cells. Classical cadherins are composed of five extracellular domains, between the individual domains, the binding sites of the calcium ions are present, which are for the adhesive function of cadherins is of fundamental importance. The interaction of Cadherinmolekülen on opposing cells ( trans-interaction ) is due to the N- terminal domains of the cells. These compounds are normally protein- specific ( homophilic ), that is an E -cadherin of a cell can bind only to E- cadherin of another cell, but not, for example, to a N- cadherin. Rarely but also heterophilic interactions between different cadherin subtypes are observed.

Non-classical cadherins are, inter alia, (Found mainly in the skin in desmosomes ) (found mainly in the skin in desmosomes ) desmocollin, desmoglein, T-cadherin (especially in the neurons and muscles).

E-cadherin

The counting of the classical cadherins E-cadherin, which is found in the epithelia, especially, is the best studied cadherin and is considered as a prototype molecule for the entire cadherin subfamily. It has 5 ECs in the extracellular domain, a transmembrane domain, and an intracellular domain which binds p120 -catenin and β -catenin. This intracellular domain has a highly phosphorylated region which is essential for the binding of β -catenin (and thus the function of E-cadherin ).

The human E-cadherin gene is located on chromosome 16q22.1, the coding region consists of 2652 base pairs.

N- cadherin

N- cadherin ( neural cadherin ) corresponds to a classical cadherin in its construction and in 1982 large as 130 kDa molecule of Grunwald from the chicken retina isolated. It plays an important role in embryonic development, since N -cadherin is formed in the early embryo in the mesoderm and notochord. However, it is detected in the late embryonic neural tissue, heart, skeletal muscle and in the lens.

In the adult organism it is formed, among others, in nerve tissue and the retina. N -cadherin stimulated by cell-cell contacts, the migration and invasion of cells and suppressed, together with the highly expressed E-cadherin in a small amount of cancer formation.

VE -cadherin

Vascular endothelial cadherin - (VE -cadherin ) is a special representative of classical cadherins, which occurs in contact points of adjacent endothelial cells. Have the contact points of endothelial cells, as opposed to those of the epithelial cells, no desmosomes. In endothelial contact points VE-cadherin fulfills the function of classical cadherins adherent contact points ( " adherens junctions" ) and desmosomal cadherins. The cytoplasmic domain binds to other classical cadherins, β -catenin, which in turn, via α -catenin regulates the actin cytoskeleton.

In the human organism more than 80 different members of the Cadherinfamilie are known. Of these, more than 30 cadherins have been identified in the developing human brain. Each cadherin has an expression pattern that is specific and is determined from the synthesis of the region and the development of the organism.

Signal transduction

Cadherin-mediated cell adhesion is a dynamic process. This process is dependent on the topology, and the stage of differentiation of the cell, but also has an effect on these. It follows that cadherins represent not only adhesion, but also important signaling molecules. The transmission of extracellular signals into the cell is accomplished through the cytoplasmic Cadherindomäne.

Catenins

Catenins are cytoplasmic proteins for which has been described as the first to be associated with classical cadherins. The family includes the catenins α - and β -catenin, γ -catenin ( plakoglobin ) and δ -catenin ( p120 catenin ). Catenins form the regulatory interface between the transmembrane cadherins and the actin filaments of the cytoskeleton in the intracellular space. The most important in carcinogenesis catenin is β -catenin, which plays a central role in the WNT signaling pathway. β - Catenin binds to both the cytoplasmic domain of classical cadherins and to α -catenin, an important regulator of the actin cytoskeleton. γ -catenin is identical to plakoglobin, a protein that was first isolated from desmosomes. How β -catenin also binds γ -catenin both to the cytoplasmic Cadherindomäne as well as to α - catenin. Another protein associated with the cytoplasmic domain of classical cadherins is p120 -catenin. p120 catenin modulating the action of cadherins, by regulating the turnover cadherin at the cell surface and, on the influence of RhoA, Rac and Cdc42, and the dynamics of the cytoskeleton.

Cadherins and cancer progression

In the progression of malignant tumors E -cadherin plays an important role, since it is the major epithelial cadherin. E-cadherin is the product of CDH1 gene. In the course of embryonic CDH1 is expressed already in Blastomerstadium. This gene product is involved in compaction of the blastomere. In the further course of E -cadherin found in all epithelia, regardless of whether they arise from ecto -, meso- or endoderm. In the majority of human carcinomas, the loss of E-cadherin on a reduced transcription of the gene by the promoter methylation of CDH1 or altered regulation is caused by transcription factors. In some types of tumors E-cadherin is inactivated by mutation of the CDH1 gene sequence. These are mainly gastrointestinal and breast cancers. Inactivating mutations of CDH1 are found mainly in those tumors in which the tumor cells spread diffusely and widely scattered. As with other Tumorsuppresorgenen most mutations of CDH1 lead to premature chain termination or the loss of larger protein segments. Most mutations lead to a chain termination, resulting in secreted E -cadherin fragments. This explains why E -cadherin in the tumor is no longer detectable. The lack of E- cadherins by carcinogenic mutation leads to ineffective binding among the tumor cells, which become detached carcinoma cells and can be worn in wide remote regions of the body through the bloodstream or lymphatic drainage, where they can form metastases. As experiments on mice in which this gene has been switched off showed that the absence of E-cadherin is not compatible with life. The embryonic development ends before the stage of blastocyst. N -cadherin deficient mice die in embryonic day 9 or 10, where the differentiation of some tissues such as the heart does not occur.