Biology Reference
In-Depth Information
Early electron microscopy of simple epithelia revealed both the complexity
and order of cell-cell adhesion junctions (Farquhar and Palade, 1965). At the
apex of the lateral membrane, the plasma membranes of adjacent cells are
closely opposed at the tight junction. The tight junction acts both as a gate to
regulate ion and solute flow in the paracellular pathway, and a fence to
regulate lipid and protein diffusion between the apical and lateral membrane
domains. Tight junction function is determined by the claudin family of
tetraspanning membrane proteins, which are linked to the actin cytoskeleton
by adapter proteins including ZO-1, -2 and -3 (Tsukita et al., 2001).
Immediately below the tight junction is located the adherens junction which
maintains cell-cell attachment and through direct linkage to a circumferential
bundle of actin filaments is also involved in regulating morphogenetic
movements of the cells during processes requiring invagination of the
monolayer in development and in wound-healing (Gumbiner, 1996). The
cadherin superfamily of transmembrane Ca
2+
-dependent cell-cell adhesion
proteins appear to initiate adhesion and maintain the organization of the
adherens junction (see below). Scattered down the lateral membrane below the
adherens junction are desmosomes composed of desmosomal cadherins that
are linked through specialized adapter proteins (desmoplakin, plakoglobin) to
intermediate filaments to form a structural continuum across the epithelial
monolayer (Green and Gaudry, 2000).
Molecular interactions and functions of classical cadherins
Initiation of cell-cell adhesion in simple epithelia appears to require a calcium-
dependent mechanism involving members of the cadherin superfamily of
proteins. Cadherins are single membrane spanning proteins with a divergent
extracellular domain of five repeats and a conserved cytoplasmic domain
(Gumbiner, 2000). Binding between extracellular domains, which requires
Ca
2+
for protein conformation (Pertz et al., 1999), is thought to involve
multiple cis-dimers of cadherin (Brieher et al., 1996; Yap et al., 1997) forming
trans-oligomers between cadherins on opposing cell surfaces (Boggon et al.,
2002). Binding between cadherin extracellular domains is weak, but strong
cell-cell adhesion develops during lateral clustering of cadherins by proteins
that link cadherin to the actin cytoskeleton (Gumbiner, 2000); b-catenin binds
to cadherin cytoplasmic domain and to a-catenin (Aberle et al., 1994; Jou
et al., 1995), which is linked directly (Rimm et al., 1995) or indirectly through
vinculin/a-actinin (Nieset et al., 1997; Hazan et al., 1997) to the actin
cytoskeleton. However, little is known about how these protein complexes
assemble in cells following initial cell-cell contact events, how the cadherin/
catenin complex binds and organizes the actin cytoskeleton, or how regulators
of the actin cytoskeleton identified at cell-cell contacts [eg. Arp2/3 (Kovacs
