Cadherin-2, originally named Neural cadherin for its role in
neural tissue, plays a role in
neurons and later was found to also play a role in
cardiac muscle and in cancer
metastasis. Cadherin-2 is a
transmembrane, 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,
cytoplasmic tails that mediate binding to
catenins, which in turn interact with the
actin cytoskeleton.
Role in development Cadherin-2 plays a role in development as a calcium dependent cell–cell adhesion
glycoprotein that functions during
gastrulation and is required for establishment of
left-right asymmetry. Cadherin-2 is widely expressed in the
embryo post-
implantation, showing high levels in the
mesoderm with sustained expression through adulthood. Cadherin-2 mutation during development has the most significant effect on cell adhesion in the primitive heart; dissociated
myocytes and abnormal heart tube development occur. Cadherin-2 plays a role in the development of the vertebrate heart at the transition of
epithelial cells to
trabecular and compact
myocardial cell layer formation. An additional study showed that
myocytes expressing a dominant negative Cadherin-2 mutant showed significant abnormalities in
myocyte 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 junctions; Cadherin-2 is an essential component in
adherens junctions, which enables cell–cell adhesion and force transmission across the
sarcolemma. 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 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 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 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 remodeling and aberrant Kv1.5 channel function. These animals showed a prolonged
action potential duration, reduced density of
inward rectifier potassium channel and decreased expression of
Kv1.5,
KCNE2 and
cortactin combined with disrupted
actin cytoskeleton at the
sarcolemma.
Role in neurons In neural cells, at certain central nervous system
synapses, presynaptic to postsynaptic
adhesion 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-catenins 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 ==