356
Cell Junctions, Structure, Function, and Regulation
of
choosing
the
appropriate
cell
type
for investigating speciFc cell functions
involving
the
regulation
of
cadherin-
mediated adhesion.
2.3.4
Other Components of Adherens
Junctions: Nectin and Afadin
In addition to the cadherin–catenin com-
plex, the AJ of many cell types including
epithelial cells, neurons and sertoli cells
contain a nectin/afadin complex that also
anchors to the actin cytoskeleton. Nectins
are a family of transmembrane proteins
that are highly homologous to human po-
liovirus receptor. There are 4 isoforms of
nectin with nectin 1, 2, and 3 having two
to three splice variants. The extracellular
domain of nectin contains three Ig-like
domains. There is a single pass transmem-
brane region coupled to a carboxyterminal
cytoplasmic tail that, in most nectins, binds
to the PDZ domain of afadin. Similar to
cadherins, nectins form cis-dimers in the
lateral plane of the membrane prior to
forming trans-dimers. Cis-dimerization is
regulated by the second Ig-like domain
in the extracellular region, while the Frst
Ig-like domain is responsible for trans-
dimer formation. In contrast to cadherins,
trans-dimerization in nectins is calcium
independent; however, nectins can form
both homo- and hetero-trans dimers.
Afadin is a cytoplasmic protein that
binds to the C-terminus of nectin. There
are two isoforms of afadin – ‘‘s’’ and ‘‘l.’’
L-afadin contains a number of domains,
including a Ras association domain, fork-
head association domain, DIL domain,
PDZ domain, three proline-rich regions,
and an actin binding domain at the C-
terminus. The ‘‘s’’ isoform contains these
same domains; however, the C-terminus
is deleted removing the third proline-rich
domain and the actin binding region.
L-afadin can bind to the side of actin
Flaments, but not to the ends, thereby
linking nectin to the actin cytoskeleton.
Afadin has been found to play an important
role in development, as knocking out this
gene results in embryonic lethalality at day
10.5. These embryos show defects at gas-
trulation including disorganization of the
ectoderm, impaired migration of the meso-
derm, and a loss of somites. Interestingly,
in afadin
/
embryos the E-cadherin lo-
calization was disrupted in the ectodermal
cell layer, but was localized to cell–cell
junctions in the endodermal layer. This
suggests that the nectina fadin complex
may be required for the formation of
cadherin-mediated junctions in certain cell
types. This is supported by studies show-
ing that the formation of nectin-mediated
junctions will recruit E-cadherin, and the
formation of cadherin-mediated junctions
will recruit nectins. The recruitment of E-
cadherin by nectin or nectin by E-cadherin
requires afadin and
α
-catenin. Although
afadin and
α
-catenin do bind to one
another, the interaction is weak, leading in-
vestigators to believe that an intermediate
protein may be required for the interaction
of E-cadherin and nectin in the AJ.
2.4
Desmosomal Cadherins and Desmosomes
Desmosomes are spot weldlike structures
that provide strong cell–cell adhesion to
tissues that require adhesive strength to
maintain organ function. When observed
by electron microscopy, desmosomes have
a very distinctive ultrastructure consisting
of two electron-dense plaques surrounding
a
lighter
central
core
(±ig. 12a).
The
central core region contains the plasma
membranes and the extracellular domains
of the desmosomal cadherins from each
of the two connected cells. Each electron-
dense band is actually a tripartite structure
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