Insights into the Role of Cell–Cell Junctions in Physiology and Disease - International Review of Cell and Molecular Biology - page 194

Of the three major cytoskeletal components (actin, microtubules, and
intermediate filaments), actin plays what may be considered the most prom-
inent role in the regulation of cell-cell contacts, by sustaining the cross-
junctional force balance, which subsequently determines cell-cell contact
patterns. Reciprocally, by providing a powerful mechanical coupling
between the actin network of adjacent cells, the cadherin-catenin complex
integrates intracellular and intercellular forces across developing tissues
( Cavey and Lecuit, 2009 ). The desmosome-intermediate filament network
helps distribute mechanical stresses throughout the embryonic tissues and
contribute to the regulation of intercellular adhesion and tissue integrity
( Brooke et al., 2012 ). Cell junctions also depend on the presence of the
microtubules, which facilitate transportation of key proteins (such as classic
and desmosomal cadherins and associated armadillo proteins) to the plasma
membrane ( Grindstaff et al., 1998; Stehbens et al., 2006 ). The ability of
developing cells to convert physical perturbations into molecular signaling
cascades, known as mechanotransduction, is based in part on the integrity of
cell junction-cytoskeletal associations ( Franke, 2009; Green et al., 2010;
Holen et al., 2012; Michaelson and Huang, 2012; Wei et al., 2011 ).

4. CELL JUNCTIONS IN DISEASE
4.1. Overview
The coordinated control of cell junctions by various signaling pathways plays
an essential role in human health and disease. Observations from a variety of
studies, including naturally occurring and engineered mutations, through
animal models and in vitro experiments, provide valuable information about
the critical functions of cell junctions and associated diseases. In recent
years, many naturally occurring human mutations have been reported in
genes that encode components of the four major cell junctional classes
( Table 5.1 ). Defects in those junctional proteins have been linked to various
inherited disorders, including skin and hair disorders, cardiomyopathies,
sensory defects, psychiatric disorders, and cancers ( Brooke et al., 2012;
El-Amraoui and Petit, 2013; Hesketh et al., 2009; Kottke et al., 2006;
Lai-Cheong et al., 2007 ). These genetic disorders also provide valuable
insight for investigating the relative contributions of mechanical stress
response and signaling pathways to the pathogenic process ( Table 5.1 ).
Many “junctional diseases” will not be discussed here; the rich diversity
of cell junction biology would perhaps make this an unreasonable ambition.
A comprehensive,

timely compendium of human genes and genetic