Cell Junctions, Structure, Function, and Regulation
347
superfamily.
Claudins,
occludins,
and
junctional adhesion molecules (JAM) are
all transmemebrane proteins that partic-
ipate in the formation of TJs. The ultra-
structures of TJs, AJs and desmosomes
all display a dense plaque region adjacent
to the plasma membrane when observed
through an electron microscope. This re-
gionappearsasadensep
laqueduetothe
large number of adaptor proteins that form
a complex that supports the function of the
transmembrane proteins (Fig. 9b). The cy-
toplasmic domains of the transmembrane
proteins bind to linker proteins that con-
nect the transmembrane proteins to the
cytoskeleton. In addition, both the cyto-
plasmic domain of the transmembrane
proteins and the linker proteins can bind
to and localize signaling proteins, such
as the Src family of tyrosine kinases, to
the junctional complex. Thus, as is the
case in focal adhesions mediated by the
integrins, cell–cell junctions too are now
considered sites that mediate inside-out or
outside-in signaling.
2.2
Cadherin Superfamily
In the early 1980s, two proteins were
being investigated for their role in medi-
ating cell–cell adhesion: uvomorulin and
L-CAM. Upon sequencing of these pro-
teins it was found that they shared a large
number of amino acids and a number
of structural features such as the require-
ment of calcium for cell–cell adhesion.
These proteins became collectively known
as E-cadherin. At this time, two other
transmembrane proteins having a similar
structure and amino acid sequence to E-
cadherin were also identi±ed: N-cadherin
and P-cadherin. Most of what is known
about cadherins has been learned from
studies of E-, N-, and P-cadherin. To date,
over 50 different cadherins have been
identi±ed in both vertebrates and inverte-
brates. The discovery of novel cadherin-like
proteins, including the recent identi±ca-
tion of the protocadherins, has lead to
the formation of the cadherin superfam-
ily containing cadherins and cadherin-
related proteins.
All members of the cadherin superfam-
ily possess cadherin homology repeats,
referred to as EC domains, in their extra-
cellular region. Cadherin-related proteins
show
a
high
degree
of
variability
in
the number of cadherin repeats in their
extracellular domain with reported num-
bers ranging from 5 to 34. In addition,
extracellular regions of cadherin-related
proteins can contain structural motifs,
such as laminin-A G repeats or EGF re-
peats, found in other proteins. A high
degree of variability also exists with re-
spect to the membrane-spanning region
of
cadherin-related
proteins.
Although
most cadherin-related proteins contain a
single spanning transmembrane region,
some members contain seven membrane-
spanning regions, while others are an-
chored to the plasma membrane by glysyl
phosphotidylinositol (GPI) linkages. The
cadherin-related proteins also show a di-
verse array of cytoplasmic tails with unique
binding domains to a wide variety of
molecules. The following discussion will
not include cadherin-related proteins due
to the variability of their structures and
functions.
The other members of the cadherin
superfamily have a number of identi-
cal structural features. These include ±ve
cadherin repeats in the extracellular do-
main, a single spanning transmembrane
region, and a highly conserved cytoplas-
mic tail. In addition, these cadherins are
synthesized as precursor molecules con-
taining a signal peptide and a propeptide
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