Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the ''CDH2''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
CDH2 has also been designated as CD325 (
cluster of differentiation 325).
Cadherin-2 is a
transmembrane
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
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
Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...
.
Structure
Cadherin-2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
with molecular weight of 99.7 kDa, and 906
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s in length. Cadherin-2, a classical
cadherin
Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...
from the cadherin superfamily, is composed of five extracellular
cadherin repeats, a
transmembrane region and a highly conserved
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
ic tail. Cadherin-2, as well as other cadherins,
interact with Cadherin-2 on an adjacent cell in an
anti-parallel conformation, thus creating a linear, adhesive "zipper" between cells.
Function
Cadherin-2, originally named Neural cadherin for its role in
neural tissue, plays a role in
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s and later was found to also play a role in
cardiac muscle and in cancer
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
. Cadherin-2 is a
transmembrane
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
, homophilic
glycoprotein belonging to the
calcium-dependent cell adhesion molecule family. These proteins have
extracellular domains that mediate homophilic interactions between adjacent cells, and
C-terminal,
cytoplasm
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
ic tails that mediate binding to
catenins, which in turn interact with
the
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
.
Role in development
Cadherin-2 plays a role in development as a calcium dependent cell–cell adhesion
glycoprotein that functions during
gastrulation
Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered embryo known as ...
and is required for establishment of
left-right asymmetry.
Cadherin-2 is widely expressed in the
embryo
An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...
post-
implantation, showing high levels in the
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...
with sustained expression through adulthood. Cadherin-2 mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociated
myocyte
A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...
s and abnormal heart tube development occur. Cadherin-2 plays a role in the development of the vertebrate heart at the transition of
epithelial cell
Epithelium or epithelial tissue is a thin, continuous, protective layer of Cell (biology), cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (Mesothelium, mesothelial) tissues line ...
s to
trabecular and compact
myocardial cell layer formation. An additional study showed that
myocyte
A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...
s expressing a dominant negative Cadherin-2 mutant showed significant abnormalities in
myocyte
A muscle cell, also known as a myocyte, is a mature contractile Cell (biology), cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal muscle, skeletal, smooth muscle, smooth, and Cardiac muscle, cardiac ...
distribution and migration towards the
endocardium, resulting in defects in trabecular formation within the
myocardium.
Role in cardiac muscle
In
cardiac muscle, Cadherin-2 is found at
intercalated disc structures which provide end-on cell–cell connections that facilitate mechanical and electrical coupling between adjacent
cardiomyocytes. Within
intercalated discs are three types of junctions:
adherens junctions,
desmosomes and
gap junction
Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites.
Gap junctions were first described as ''close appositions'' alongside tight ...
s; Cadherin-2 is an essential component in
adherens junctions, which enables cell–cell adhesion and force transmission across the
sarcolemma
The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath), also called the myolemma, is the cell membrane surrounding a skeletal muscle fibre or a cardiomyocyte.
It consists of a lipid bilayer and a thin ...
. Cadherin-2 complexed to
catenins has been described as a master regulator of
intercalated disc function. Cadherin-2 appears at cell–cell junctions prior to
gap junction
Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites.
Gap junctions were first described as ''close appositions'' alongside tight ...
formation, and is critical for normal
myofibrillogenesis. Expression of a mutant form of Cadherin-2 harboring a large deletion in the
extracellular domain inhibited the function of endogenous Cadherin-2 in adult
ventricular cardiomyocytes, and neighboring cardiomyocytes lost cell–cell contact and
gap junction
Gap junctions are membrane channels between adjacent cells that allow the direct exchange of cytoplasmic substances, such small molecules, substrates, and metabolites.
Gap junctions were first described as ''close appositions'' alongside tight ...
plaques as well.
Mouse models employing transgenesis have highlighted the function of N-cadherin in
cardiac muscle. Mice with altered expression of N-cadherin and/or E-cadherin showed a
dilated cardiomyopathy phenotype, likely due to malfunction of
intercalated discs. In agreement with this, mice with ablation of N-cadherin in adult hearts via a cardiac-specific tamoxifen-inducible Cre N-cadherin transgene showed disrupted assembly of
intercalated discs,
dilated cardiomyopathy, impaired cardiac function, decreased
sarcomere
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal striated muscle, Skeletal muscles are composed of tubular ...
length, increased
Z-line thickness, decreases in
connexin 43, and a loss in muscular tension. Mice died within two months of transgene expression, mainly due to spontaneous
Ventricular tachycardia. Further analysis of N-cadherin knockout mice revealed that the
arrhythmias were likely due to
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
remodeling and aberrant Kv1.5 channel function. These animals showed a prolonged
action potential
An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
duration, reduced density of
inward rectifier potassium channel and decreased expression of
Kv1.5,
KCNE2 and
cortactin combined with disrupted
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
at the
sarcolemma
The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath), also called the myolemma, is the cell membrane surrounding a skeletal muscle fibre or a cardiomyocyte.
It consists of a lipid bilayer and a thin ...
.
Role in neurons
In neural cells, at certain central nervous system
synapse
In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
s, presynaptic to postsynaptic
adhesion
Adhesion is the tendency of dissimilar particles or interface (matter), surfaces to cling to one another. (Cohesion (chemistry), Cohesion refers to the tendency of similar or identical particles and surfaces to cling to one another.)
The ...
is mediated at least in part by Cadherin-2. N-cadherins interact with catenins to play an important role in learning and memory (''For full article see
Cadherin-catenin complex in learning and memory''). Loss of N-cadherin is also associated with attention-deficit hyperactivity disorder in humans, and impaired synaptic functioning.
Role in cancer metastasis
Cadherin-2 is commonly found in cancer cells and provides a mechanism for transendothelial migration. When a cancer cell adheres to the endothelial cells of a blood vessel it up-regulates the
src kinase pathway, which phosphorylates
beta-catenin
Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
s attached to both Cadherin-2 (this protein) and
E-cadherins. This causes the intercellular connection between two adjacent endothelial cells to fail and allows the cancer cell to slip through.
Clinical significance
Variants in ''CDH2'' have been identified to cause a syndromic
neurodevelopmental disorder
Neurodevelopmental disorders are a group of mental conditions negatively affecting the development of the nervous system, which includes the brain and spinal cord. According to the American Psychiatric Association Diagnostic and Statistical Manu ...
characterized by
Corpus callosum
The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...
, axon, cardiac, ocular, and genital differences.
One study investigating genetic underpinnings of
obsessive-compulsive disorder and
Tourette disorder found that while ''CDH2'' variants are likely not disease-causing as single entities, they may confer risk when examined as part of a panel of related cell–cell adhesion genes. Further studies in larger cohorts will be required to unequivocally determine this.
In human
dilated cardiomyopathy, it was shown that Cadherin-2 expression was enhanced and arranged in a disarrayed fashion, suggesting that disorganization of Cadherin-2 protein in
heart disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...
may be a component of remodeling.
Interactions
Cadherin-2 has been shown to
interact with:
*
Beta-catenin
Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
,
*
CDH11,
[
* type IIb RPTPs including PTPmu ( CTNND1),][
* CTNNA1,][
* LRRC7,]
* PTPRM)
* PTPrho ( PTPRT), and
* Plakoglobin.
* XIRP1
* SCARB2
See also
* ADH-1
References
Further reading
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External links
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{{Cell adhesion molecules
Clusters of differentiation