Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1042 Chapter 19: Cell Junctions and the Extracellular Matrix
Epithelial–Mesenchymal Transitions Depend on Control of
Cadherins
The assembly of cells into an epithelium is a reversible process. By switching on
expression of adhesion molecules, dispersed unattached mesenchymal cells, such
as fibroblasts, can come together to form an epithelium. Conversely, epithelial
cells can change their character, disassemble, and migrate away from their parent
epithelium as separate cells. Such epithelial–mesenchymal transitions play an
important part in normal embryonic development; the origin of the neural crest
is one example. These transitions depend in part on transcription regulatory proteins
called Slug, Snail, and Twist. Increased expression of Twist, for example,
converts epithelial cells to a mesenchymal character, and switching it off does the
opposite. Twist exerts its effects, in part, by inhibiting expression of cadherins,
including E-cadherin, that hold epithelial cells together.
Epithelial–mesenchymal transitions also occur as pathological events during
adult life, in cancer. Most cancers originate in epithelia, but become dangerously
prone to spread—that is, malignant—only when the cancer cells escape from the
epithelium of origin and invade other tissues. Experiments with malignant breast
cancer cells in culture show that blocking expression of Twist can convert the cells
back toward a nonmalignant character. Conversely, by forcing Twist expression,
one can make normal epithelial cells undergo an epithelial–mesenchymal transition
and behave like malignant cells. Mutations that disrupt the production or
function of E-cadherin are often found in cancer cells and are thought to help
make them malignant.
Catenins Link Classical Cadherins to the Actin Cytoskeleton
The extracellular domains of cadherins mediate homophilic binding at adherens
junctions. The intracellular domains of typical cadherins, including all classical
and some nonclassical ones, interact with filaments of the cytoskeleton: actin at
adherens junctions and intermediate filaments at desmosomes (see Table 19–1).
These cytoskeletal linkages are essential for efficient cell–cell adhesion, as cadherins
that lack their cytoplasmic domains cannot stably hold cells together.
The linkage of cadherins to the cytoskeleton is indirect and depends on adaptor
proteins that assemble on the cytoplasmic tail of the cadherin. At adherens
junctions, the cadherin tail binds two such proteins: β-catenin and a distant relative
called p120-catenin; a third protein called α-catenin interacts with β-catenin
and recruits a variety of other proteins to provide a dynamic linkage to actin
filaments (Figure 19–10). At desmosomes, cadherins are linked to intermediate
filaments through other adaptor proteins, including a β-catenin-related protein
called plakoglobin, as we discuss later.
In their mature form, adherens junctions are enormous protein complexes
containing hundreds to thousands of cadherin molecules, packed into dense, regular
arrays that are linked on the extracellular side by lateral interactions between
cadherin domains, as we discussed earlier (see Figure 19–6C). On the cytoplasmic
side, a complex network of catenins, actin regulators, and contractile actin bundles
holds the cluster of cadherins together and links it to the actin cytoskeleton.
Assembling a structure of this complexity is not a simple task, and it involves a
complex sequence of events controlled by the actin-regulatory proteins discussed
in Chapter 16. The general features of the assembly process are summarized in
Figure 19–11.
Adherens Junctions Respond to Forces Generated by the Actin
Cytoskeleton
Most adherens junctions are linked to contractile bundles of actin filaments and
non-muscle myosin II. These junctions are therefore subjected to pulling forces
generated by the attached actin. The pulling forces are important for junction
assembly and maintenance: disruption of myosin activity, for example, results in
plasma membrane
p120-catenin
β-catenin
α-catenin
actin
filaments
cadherin
CYTOSOL
vinculin
Figure 19–10 The linkage of classical
cadherins to actin filaments. The
cadherins are coupled indirectly to actin
filaments through an adaptor protein
MBoC6 m19.14/19.10
complex containing p120-catenin,
β-catenin, and α-catenin. Other proteins,
including vinculin, associate with α-catenin
and help provide the linkage to actin.
β-Catenin has a second, and very
important, function in intracellular signaling,
as we discuss in Chapter 15 (see Figure
15–60). For clarity, this diagram does not
show the cadherin of the adjacent cell in
the junction.