CHARACTERIZATION OF THE ADHESIVE INTERACTIONS BETWEEN CELLS AND BIOMATERIALS - Micro and Nanotechnologies in Engineering Stem Cells and Tissues - page 164

7.2.2 Cadherins

Cadherins are a superfamily of glycoproteins that function to mediate cell-to-cell
adhesions. Most cadherins are composed of an extracellular domain that sets up
interactions among neighboring cells, a transmembrane domain, and a cytoplasmic
domain, which is often linked to the elements of the cytoskeleton. 18 Cadherins are
calcium-dependent molecules, and the calcium-binding domain is conserved
throughout the various types of cadherins within the superfamily. 19 Because of
the involvement of cell-to-cell adhesion in numerous cellular processes, cadherins
have been found to contribute to cell signaling, recognition, and sorting in addition to
cell adhesion. Alterations to normal cadherin function have been linked to several
diseases, particularly cancer.
The cadherin superfamily can be divided into at least six subclasses. The oldest
and most well understood are the classical cadherins: E-, N-, and P-cadherins as well
as VE-cadherin. Classical cadherins are single spanning transmembrane proteins that
primarily function in the formation of adherens junctions. Adherens junctions are
typically located on epithelial cells and are formed by the interaction of classical
cadherins. 20 E-cadherin is primarily associated with adherens junctions, but similar
structures exist in a variety of epithelial cell types; for example, in squamous
epithelial cells, both E- and P-cadherin independently form adherens junctions. 21
The cytoplasmic domain of adherens junctions bind to b -catenin or plakoglobin,

which in turn bind to -Catenin links the cadherin-catenin complex to the

actin cytoskeleton either through direct binding to actin or indirect binding to
vinculin, ZO-1, or

a -catenin. a

-actinin, which leads to actin binding. 20 Evidence has shown that
lateral clustering of cadherins occurs in the formation of adherens junctions and that
the redistribution of cadherin binding sites is a means to regulate cell adhesion as
well as stimulate a stronger adhesion between cells. 22
The classical cadherins also play a vital role in development. It has been shown
that N-cadherin functions in neural development, including retina development and
the formation of neural nodes and neural networks. Recently, attempts to mimic the
N-cadherin structure present during neural development has shown promising
results, including induction of the differentiation of neural stem cells and desirable
cell-cell interaction. 23
Desmosomal cadherins function in the formation of desmosomes and are one of
the few types of cadherins that bind to the intermediate filaments of the cytoskeleton
rather than actin. Desmocollin and desmoglein are the two subfamilies of the
desmosomal cadherins. Tissues that undergo mechanical stress, such as the epi-
dermis and the myocardium, are rich in desmosomes. 19 Structurally similar to
adherens junctions, desmosomes link to the intermediate filaments of the cyto-
skeleton. Desmosomes are the result of a heterotropic interaction between one
desmocollin and one desmoglein cadherin. The cytoplasmic domains of desmosomes
directly link to plakoglobin, which binds to a second intermediate protein, desmo-
plakin. 24 Desmoplakin forms the connection between the cadherin complex and
keratin intermediate filaments. 25 Similar to adherens junctions, evidence indicates
that desmosomal cadherins cluster to form desmosomes. 26 Desmosome expression

a