Review
Molecular evolution of the cadherin superfamily

https://doi.org/10.1016/j.biocel.2008.09.027Get rights and content

Abstract

This review deals with the large and pleiotropic superfamily of cadherins and its molecular evolution. We compiled literature data and an in-depth phylogenetic analysis of more than 350 members of this superfamily from about 30 species, covering several but not all representative branches within metazoan evolution. We analyzed the sequence homology between either ectodomains or cytoplasmic domains, and we reviewed protein structural data and genomic architecture. Cadherins and cadherin-related molecules are defined by having an ectodomain in which at least two consecutive calcium-binding cadherin repeats are present. There are usually 5 or 6 domains, but in some cases as many as 34. Additional protein modules in the ectodomains point at adaptive evolution. Despite the occurrence of several conserved motifs in subsets of cytoplasmic domains, these domains are even more diverse than ectodomains and most likely have evolved separately from the ectodomains. By fine tuning molecular classifications, we reduced the number of solitary superfamily members. We propose a cadherin major branch, subdivided in two families and 8 subfamilies, and a cadherin-related major branch, subdivided in four families and 11 subfamilies. Accordingly, we propose a more appropriate nomenclature. Although still fragmentary, our insight into the molecular evolution of these remarkable proteins is steadily growing. Consequently, we can start to propose testable hypotheses for structure–function relationships with impact on our models of molecular evolution. An emerging concept is that the ever evolving diversity of cadherin structures is serving dual and important functions: specific cell adhesion and intricate cell signaling.

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.

Section snippets

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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