Cadherin

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Principal interactions of structural proteins at cadherin-based adherens junction. Actin filaments are linked to a-actinin and to the membrane through vinculin. The head domain of vinculin is associated with E-cadherin via a-, b-, and g-catenins. The tail domain of vinculin binds to membrane lipids and to actin filaments. Adherens Junctions structural proteins.svg
Principal interactions of structural proteins at cadherin-based adherens junction. Actin filaments are linked to α-actinin and to the membrane through vinculin. The head domain of vinculin is associated with E-cadherin via α-, β-, and γ-catenins. The tail domain of vinculin binds to membrane lipids and to actin filaments.

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.

Contents

Background

The cadherin family is essential in maintaining cell-cell contact and regulating cytoskeletal complexes. 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 molecules, each designated with a prefix for tissues with which it associates. Classical cadherins maintain the tone of tissues by forming a homodimer in cis, while desmosomal cadherins are heterodimeric. [4] 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 -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. [4] Atypical cadherins, such as CELSR1, retain the extracellular repeats and binding activities of the other cadherins, but may otherwise differ significantly in structure, and are typically involved in transmitting developmental signals rather than adhesion. [5]

Cells containing a specific cadherin subtype tend to cluster together to the exclusion of other types, both in cell culture and during development. [6] For example, cells containing N-cadherin tend to cluster with other N-cadherin-expressing cells. However, mixing speed in cell culture experiments can effect the extent of homotypic specificity. [7] In addition, several groups have observed heterotypic binding affinity (i.e., binding of different types of cadherin together) in various assays. [8] [9] 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. [10]

Structure

Domain organization of different types of cadherins Protocadherins image2.png
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. [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, -catenin,  -catenin, and vinculin. Binding of p-120 catenin and -catenin to the homodimer increases the stability of the classical cadherin. -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 -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. [15] In the very early stages of development, E-cadherins (epithelial cadherin) are 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 a neural plate forms in an embryo, the tissues residing near the cranial neural folds have decreased N-cadherin expression. [16] Conversely, the expression of the N-cadherins remains unchanged in other regions of the neural tube that is located on the anterior-posterior axis of the vertebrate. [16] N-cadherins have different functions that maintain the cell structure, cell-cell adhesion, internal adhesions. They participate greatly in keeping the ability of the structured heart due to pumping and release blood. Because of the contribution of N-cadherins adhering strongly between the cardiomyocytes, the heart can overcome the fracture, deformation, and fatigue that can result from the blood pressure. [17] N-cadherin takes part in the development of the heart during embryogenesis, especially in sorting out of the precardiac mesoderm. N-cadherins are robustly expressed in precardiac mesoderm, but they do not take a role in cardiac linage. An embryo with N-cadherin mutation still forms the primitive heart tube; however, N-cadherin deficient mice will have difficulties in maintaining the cardiomyocytes development. [17] The myocytes of these mice will end up with dissociated myocytes surrounding the endocardial cell layer when they cannot preserve the cell adhesion due to the heart starting to pump. As a result, the cardiac outflow tract will be blocked causing cardiac swelling. The expression of different types of cadherins in the cells varies dependent upon the specific differentiation and specification of an organism during development. Cadherins play a vital role in the migration of cells through the epithelial–mesenchymal transition, 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. [16] In addition, cadherins that are responsible in the epithelial–mesenchymal transition 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. [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 catenins. CAMs such as the cadherin glycoproteins that normally function as the glue and holds cells together 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. [22]

Correlation to endometrium and embryogenesis

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

Cadherin domain (repeat)
ECadherin repeating unit.png
Ribbon representation of a repeating unit in the extracellular E-cadherin ectodomain of the mouse ( PDB: 3Q2V ​) [25]
Identifiers
SymbolCadherin
Pfam PF00028
InterPro IPR002126
SMART CA
PROSITE PDOC00205
SCOP2 1nci / SCOPe / SUPFAM
Membranome 114
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
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. [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.

Desmosomal

Protocadherins

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

Unconventional/ungrouped

See also

Related Research Articles

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

<span class="mw-page-title-main">Cell junction</span> Multiprotein complex that forms a point of contact or adhesion in animal cells

Cell junctions or junctional complexes are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also maintain the paracellular barrier of epithelia and control paracellular transport. Cell junctions are especially abundant in epithelial tissues. Combined with cell adhesion molecules and extracellular matrix, cell junctions help hold animal cells together.

<span class="mw-page-title-main">Catenin</span> Type of protein

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

<span class="mw-page-title-main">Adherens junction</span> Protein complexes at cell junctions

In cell biology, adherens junctions are protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissues, usually more basal than tight junctions. An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell or as spots of attachment to the extracellular matrix.

<span class="mw-page-title-main">Desmoglein-2</span> Protein found in humans

Desmoglein-2 is a protein that in humans is encoded by the DSG2 gene. Desmoglein-2 is highly expressed in epithelial cells and cardiomyocytes. Desmoglein-2 is localized to desmosome structures at regions of cell-cell contact and functions to structurally adhere adjacent cells together. In cardiac muscle, these regions are specialized regions known as intercalated discs. Mutations in desmoglein-2 have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy.

<span class="mw-page-title-main">Catenin beta-1</span> Mammalian protein found in humans

Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

<span class="mw-page-title-main">Plakoglobin</span> Mammalian protein found in Homo sapiens

Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.

α-Catenin Primary protein link between cadherins and the actin cytoskeleton

α-Catenin (alpha-catenin) functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and α-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. α-Catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, β-catenin and α-catenin has not been isolated.

<span class="mw-page-title-main">Cadherin-2</span> Protein found in humans

Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 . Cadherin-2 is a transmembrane protein expressed in multiple tissues and functions to mediate cell–cell adhesion. In cardiac muscle, Cadherin-2 is an integral component in adherens junctions residing at intercalated discs, which function to mechanically and electrically couple adjacent cardiomyocytes. Alterations in expression and integrity of Cadherin-2 has been observed in various forms of disease, including human dilated cardiomyopathy. Variants in CDH2 have also been identified to cause a syndromic neurodevelopmental disorder.

p120 catenin Protein found in humans

p120 catenin, or simply p120, also called catenin delta-1, is a protein that in humans is encoded by the CTNND1 gene.

<span class="mw-page-title-main">CDH3 (gene)</span> Protein-coding gene in the species Homo sapiens

Cadherin-3, also known as P-Cadherin, is a protein that in humans is encoded by the CDH3 gene.

<span class="mw-page-title-main">Epithelial cell adhesion molecule</span> Transmembrane glycoprotein

Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.

<span class="mw-page-title-main">DSC2</span> Protein-coding gene in humans

Desmocollin-2 is a protein that in humans is encoded by the DSC2 gene. Desmocollin-2 is a cadherin-type protein that functions to link adjacent cells together in specialized regions known as desmosomes. Desmocollin-2 is widely expressed, and is the only desmocollin isoform expressed in cardiac muscle, where it localizes to intercalated discs. Mutations in DSC2 have been causally linked to arrhythmogenic right ventricular cardiomyopathy.

<span class="mw-page-title-main">PTPRM</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

<span class="mw-page-title-main">Cadherin-1</span> Human protein-coding gene

Cadherin-1 or Epithelial cadherin(E-cadherin), is a protein that in humans is encoded by the CDH1 gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. CDH1 has also been designated as CD324. It is a tumor suppressor gene.

<span class="mw-page-title-main">Catenin alpha-1</span> Protein found in humans

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

<span class="mw-page-title-main">VEZT</span> Protein-coding gene in the species Homo sapiens

VEZT is a gene located on chromosome 12 and encodes for the protein vezatin. Vezatin is a major component of the cadherin-catenin complex that is critical to the formation and maintenance of adherens junctions. The protein is expressed in most epithelial cells and is crucial to the formation of cell-cell contact junctions. Mutations of the gene can lead to upregulation or downregulation of the protein which can have detrimental effects on physiological systems, particularly those involved in development.

Epithelial polarity is one example of the cell polarity that is a fundamental feature of many types of cells. Epithelial cells feature distinct 'apical', 'lateral' and 'basal' plasma membrane domains. Epithelial cells connect to one another via their lateral membranes to form epithelial sheets that line cavities and surfaces throughout the animal body. Each plasma membrane domain has a distinct protein composition, giving them distinct properties and allowing directional transport of molecules across the epithelial sheet. How epithelial cells generate and maintain polarity remains unclear, but certain molecules have been found to play a key role.

Cell–cell interaction refers to the direct interactions between cell surfaces that play a crucial role in the development and function of multicellular organisms. These interactions allow cells to communicate with each other in response to changes in their microenvironment. This ability to send and receive signals is essential for the survival of the cell. Interactions between cells can be stable such as those made through cell junctions. These junctions are involved in the communication and organization of cells within a particular tissue. Others are transient or temporary such as those between cells of the immune system or the interactions involved in tissue inflammation. These types of intercellular interactions are distinguished from other types such as those between cells and the extracellular matrix. The loss of communication between cells can result in uncontrollable cell growth and cancer.

References

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