The International Journal of Biochemistry & Cell Biology
ReviewMolecular evolution of the cadherin superfamily
Introduction
Cadherins and proteins with typical cadherin domains are found in an amazingly wide range of organisms, ranging from unicellular choanoflagellates to invertebrates and all classes of vertebrates. For so-called classic cadherins, such as E-cadherin, the primary role is cell–cell adhesion that is generally but not always of the homophilic type (between identical molecules). However, even E-cadherin cannot be considered merely ‘molecular glue’ as it has been associated with numerous signaling events with major implications for embryonic development, tissue morphogenesis and homeostasis (reviewed in van Roy and Berx, 2008). This makes sense because multicellularity implies not only that particular cells adhere to each other in a specific way, but also that such adhesion leads to coordination in cell behavior through cell–cell signaling and spatiotemporal control of differential gene expression.
We previously reported on the phylogenetic analysis of the cadherin superfamily and proposed its subdivision into six major subfamilies (Nollet et al., 2000). Since then, much more sequence information became available, thanks to several large-scale comparative genome sequencing projects as well as from dedicated analyses of cadherin and cadherin-related genes and proteins. Over 20,000 cadherin protein sequences have been deposited in Genbank, and about 1400 cadherin genes can be found in Entrez Gene in a wide variety of metazoan species. In view of the 200th anniversary of Charles Darwin’s birth, it is proper to update and extend our evolutionary view of the cadherin superfamily. This detailed sequence comparison of cadherins in a variety of model organisms also forms a solid basis for structural analysis of different cadherin types and for interesting functional correlates.
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Structural knowledge of cadherins
The first two structures of cadherin family members were reported in 1995: the amino-terminal domain of E-cadherin (CDH1) was determined by NMR (Overduin et al., 1995), and the crystal structure of the first cadherin domain of murine N-cadherin (CDH2) was solved (Shapiro et al., 1995). An overview of these cadherin structures and of others discussed here is listed in Table 1. The extracellular domains of cadherins, which are transmembrane glycoproteins, are characterized by the presence of two
Phylogenetic analysis of cadherins
Cadherins are calcium-dependent membrane proteins that have an ectodomain consisting of five cadherin motifs and a cytoplasmic domain with two conserved motifs, unlike several cadherin-related molecules, which were defined by Sano et al. (1993) as protocadherins on the basis of shared properties. Other cadherin-like proteins not meeting this stringent cadherin definition and also lacking typical protocadherin features, but nevertheless still having the typical cadherin repeats with conserved
Cadherin gene architecture
Similar gene architectures, i.e. exon–intron structures, of homologous genes indicate a closer evolutionary relationship. We previously compared the gene structures of human classical cadherins, desmosomal cadherins and protocadherins (Nollet et al., 2000). For the present review we compared members of these families with selected genes from other families within the cadherin superfamily. Genomic views gathered from the UCSC Genome Browser are listed in Suppl. Figs. 25–27. In these views, exons
Non-metazoan cadherin-like domains
We included two non-metazoan organisms, the choanoflagellate M. brevicollis and the amoeba Dictyostelium discoideum, in the cladogram of Fig. 3 because putative cadherin genes have been identified in their genomes (Abedin and King, 2008, Wong et al., 1996).
In the genome of M. brevicollis, 23 genes containing cadherin-like domains were reported (Suppl. Table 1a) (Abedin and King, 2008). Only 10 of these were included in our analyses. The others either missed the conserved LDRE-like and DxND-like
The premetazoan ancestry of cadherins
Although we realize that many gaps remain in our evolutionary view of the cadherin superfamily, which may be filled thanks to recently finished and ongoing genome projects and accompanying in-depth annotations, we can already draw some conclusions on major steps in cadherin evolution. However, in view of the continued release of these ever growing genomic sequence data, functional annotations are lagging behind, and structure–function studies on gene products lag even further behind. Basic data
Concluding remarks
This literature overview and phylogenetic analysis of the growing superfamily of cadherin and cadherin-related proteins is by no means exhaustive. Nonetheless, it contributes to a better understanding of the molecular evolution of this large, versatile and intriguing protein superfamily. The many recently finished as well as ongoing genome sequencing projects will allow a more thorough analysis in the upcoming years, provided they are complemented by comprehensive structure–function analyses.
Acknowledgments
This research was funded by grants from the FWO, the Geconcerteerde Onderzoeksacties of Ghent University, and the Belgian Federation against Cancer. We acknowledge Prof. Dominique Adriaens, Ph.D. (Department of Biology, Ghent University) for expert advice on taxonomy, including Fig. 3. We thank Dr. Amin Bredan for critical reading and extensive editing of the manuscript.
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