Cadherin

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.[1] 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 numerous adaptor and signaling proteins, collectively referred to as the cadherin adhesome.

Principal interactions of structural proteins at cadherin-based adherens junction. Actin filaments are linked to α-actinin and to membrane through vinculin. The head domain of vinculin associates to E-cadherin via α-, β-, and γ-catenins. The tail domain of vinculin binds to membrane lipids and to actin filaments.

The cadherin superfamily includes cadherins, protocadherins, desmogleins, desmocollins, and more.[2][3] 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.[4] 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.[5] In addition, several groups have observed heterotypic binding affinity (i.e., binding of different types of cadherin together) in various assays.[6][7] 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.[8]

Structure
Domain organization of different types of cadherins

Cadherins are synthesized as polypeptides and undergo many post-translational modifications to become the proteins which mediate cell-cell adhesion and recognition.[9] 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.[10]  Because cadherins are Ca2+ dependent, they have five tandem extracellular domain repeats that act as the binding site for Ca2+ ions.[11]  Their extracellular domain interacts in two separate trans dimer conformations: strand-swap dimers (S-dimers) and X-dimers.[11] To date, over 100 types of cadherins in humans have been identified and sequenced.[12]

 The functionality of cadherins relies upon the formation of two identical subunits, known as homodimers.[10] 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.[10] 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.[10]

Function

Development

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.[13] 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.[14] 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.[14] 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 form 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 cadherins are necessary to allow migration of cells to form tissues or organs.[14] 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 (iPSCs).[1]

After development, cadherins play a role in maintaining cell and tissue structure, and in cellular movement.[12] Regulation of cadherin expression can occur through promoter methylation among other epigenetic mechanisms.[15]

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.[16] 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 of its important role tumor suppression, E-cadherin is also referred to as the "suppressor of invasion".[17]

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 also known as the epithelial cadherins on the surface of one cell can bind with those of the same kind on another to form bridges.[18] It is indicated that the loss of the cell adhesion molecule E cadherin is causally involved in the formation of epithelial types of cancers such as carcinomas. The changes in any type of cadherin expression may not only control tumor cell adhesion but also affect signal transduction leading to the cancer cells growing uncontrollably.[19]


In epithelial cell cancers, disrupted cell to cell adhesion might lead to the development of secondary malignant growths that are distant from the primary site of cancer, can result from the abnormalities in the expression of E-cadherins or its associated catenins. CAMs such as the cadherin glycoproteins normally function as the glue that holds cells together and act as important mediators of cell to cell interactions. E-cadherins, on the surface of all epithelial cells, are linked to the actin cytoskeleton through interactions with catenins in the cytoplasm. Thus, anchored to the cytoskeleton, E-cadherins on the surface of one cell can bind with those on another to form bridges. In epithelial cell cancers, disrupted cell-cell adhesion that might lead to metastases can result from abnormalities in the expression of E-cadherin or its associated catenins.[18]

Correlation to endometrium and embryogenesis

This family of glycoproteins are 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-cadherin impairs intracellular adhesion. The levels of this molecule increases during the luteic phase, while its expression is regulated by progesterone with endometrial calcitonin.[20]

Types
Cadherin domain (repeat)
Ribbon representation of a repeating unit in the extracellular E-cadherin ectodomain of the mouse (PDB: 3Q2V​) [21]
Identifiers
SymbolCadherin
PfamPF00028
InterProIPR002126
SMARTCA
PROSITEPDOC00205
SCOP21nci / SCOPe / SUPFAM
Membranome114
See Pfam CL0159 for other Cadherin families.

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.[22][23] 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.[23]

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.
  • 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

Protocadherins
Main article: Protocadherin

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

Unconventional/ungrouped
  • CDH4 – R-cadherin (retinal)
  • CDH5 – VE-cadherin (vascular endothelial)
  • CDH6 – K-cadherin (kidney)
  • CDH7 – cadherin 7, type 2
  • CDH8 – cadherin 8, type 2
  • CDH9 – cadherin 9, type 2 (T1-cadherin)
  • CDH10 – cadherin 10, type 2 (T2-cadherin)
  • 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)
  • CDH22, CDH24, CDH26, CDH28
  • CELSR1, CELSR2, CELSR3
  • CLSTN1, CLSTN2, CLSTN3
  • DCHS1, DCHS2,
  • LOC389118
  • PCLKC
  • RESDA1
  • RET

See also

References
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Further reading
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