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Cadherins constitute a large superfamily of cell surface receptors, many of which function in calcium-dependent cell-cell recognition and adhesion. Cadherins are found in a wide array of species ranging from unicellular animals with multicellular life stages to mammals, in which they are involved in morphogenetic processes such as embryonic cell layer separation, cell signaling, synapse formation and specificity in the central nervous system, mechanotransduction, and physical homeostasis of mature tissues. Consistent with these roles, decreased cadherin expression, which may allow cells to escape normal viability requirements for cellular cohesion, is a common feature of metastasis.
The molecular hallmark of cadherins is so-called cadherin repeats in the extracellular domain that are each approximately 100 amino acids long. In humans, over 100 cadherin-related genes exist. Many of the genes of the cadherin superfamily are organized in clusters, which have been mapped to human chromosomes 5q13–15, 5p14–15, 5q31–32, 13q14.3–21.1, 16q22.1, 16q24.1 and 18q12.1. There are several subfamilies of cadherins that share specific structural features and sequence motifs, especially in their cytoplasmic domain, which interacts with signaling molecules. Due to these shared features, it is probably that gene duplication, reverse transcription and gene translocation contributed to the diversity of the cadherin superfamily.
The classical cadherin family
Members of the cadherin superfamily are defined by a common structural component, the EC domain – an about 110 residues β-fold domain – and cadherins can be classified into multiple subfamilies based on the number and arrangement of EC domains. By far the best understood of these subfamilies are the vertebrate classical cadherins, comprising six ‘type I’ and 13 ‘type II’ cadherins in typical vertebrate genomes, which share a conserved cytoplasmic domain and an ectodomain containing five tandem EC domains. Linkers between successive EC domains are each stabilized by the binding of three Ca2+ ions leading to a characteristic curvature of the ectodomain (Figure 1).
Figure 1. Schematic representation of members of the cadherin family
Classical cadherins provide the prototypical example of calcium-dependent homophilic cell-cell adhesion. They are often concentrated at adherens junctions, specialized cell-cell adhesion structures characterized by parallel apposed plasma membranes with an intermembrane space of approximately 15–30 nm. In these junctions, cadherins form trans bonds bridging the intermembrane space by their ectodomains, while their cytoplasmic domains bind to the adaptor proteins β-catenin, which links cadherins indirectly to the cytoskeleton, and p120 catenin which regulates cadherin turnover and modulates actin assembly.
Cadherins and cancer
The epithelial cell-cell adhesion molecule cadherin 1 (CDH1) is a well-known growth and invasion suppressor. In normal tissues, CDH1 is mainly expressed by epithelial cells, which are the progenitors of carcinomas. CDH1 has been considered to be a paradigmatic classical cadherin. CDH1 is known to suppress tumorigenicity and tumor dissemination through complex mechanisms that promote tissue organization and block apoptosis. These mechanisms are thought to involve biophysical adhesion processes and mechanotransduction-based intracellular signaling coupled to inhibition of proto-oncogenic molecules such as β‑catenin and epidermal growth factor receptor (EGFR). Malignant carcinoma cells abrogate CDH1 function in numerous ways. Nevertheless, phylogenetic studies have shown that in mammals CDH1 is just one of more than 110 cadherin superfamily members, many of which are still poorly studied. Since structural diversity is a basis for functional specificity, one wonders whether other cadherins also have the tumor-suppressing activity or otherwise function synergistically or antagonistically with respect to CDH1, or whether they have completely separate tumor-related roles.
The growing data show that other members of the cadherin superfamily besides CDH1 undergo cancer-related changes and affect tumorigenesis and/or tumor progression. Whether such cadherins function as oncogenic or tumor suppressor proteins depend not only on the identity of the cadherin but also on the tumor type, cell type and most importantly on the tissue contexts of both the primary and the disseminated tumors. Heterotypic contacts between cancer cells and tumor-associated cells are mediated by cadherins and generate extensive crosstalk, whereas both homophilic and heterophilic binding in cis or trans provide the cadherin types with a number of possible functions. A recurrent theme is the influence of various cadherins on receptor tyrosine kinases and integrins, as well as the signaling pathways that are associated with them. Cadherin switches have often been observed during EMT and cancer progression, but the biological response can be modified by co‑expression of different cadherin types, whether they are members of the same cadherin subfamily or more distantly related members. The reversion or induction of complex cancer cell phenotypes through either restoring or silencing particular cadherins makes these cadherins potential therapeutic targets, but the emerging and often poorly predictable interactivities of various cadherins could also make such targeted therapies challenging and risky.
Figure 2. Characteristic molecular interactions and biological activities of representative members of the cadherin superfamily within cancer cells.
Cadherins and neuropsychiatric disorders
Cadherins play a role during morphogenesis of most, if not all tissues and organs in multicellular organisms. In the vertebrate embryo, cadherin deficits are typically associated with organ malformation. In the mature organism, loss of cadherin function can cause tumorigenesis, in part, because cells lose their adhesive properties, detach from the surrounding cells and become invasive. The vast majority of cadherin types are also expressed in the developing and mature vertebrate brain. Mature brain function is based on neural circuitry that has its origin in the early embryonic patterning and functional differentiation of the neural tube. Cadherins represent potentially adhesive cues which are involved at all levels of functional brain specification, from early embryonic patterning to circuit formation, synaptogenesis and synaptic plasticity in the mature brain. In the nervous system, cadherins play key roles in neural tube regionalization, neuronal migration, gray matter differentiation, spine morphology, neural circuit formation, and synapse formation and remodeling. In addition to disease-causing mutations, sequence variants within or near cadherin genes have been associated with an increased risk for neuropsychiatric disorders.
Several studies have shown an association of cadherins with neuropsychiatric disease. However, these studies should still be taken with caution because coding and regulatory mutations have not yet been identified at present, with the notable exception of PCDH19. Cadherins represent a complex code of (potentially) adhesive cues regulating the emergence of functional neural circuitry during vertebrate brain development and mature synaptic function. In general, given their pivotal role in nervous system development and synaptic function, cadherins represent promising candidate genes to study in the context of neuropsychiatric disorders.