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.
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.
References (108)
- et al.
Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site
J Biol Chem
(2001) - et al.
Heterotypic trans-interaction of LI- and E-cadherin and their localization in plasmalemmal microdomains
J Mol Biol
(2008) - et al.
The structure of the N-terminal region of murine skeletal muscle alpha-dystroglycan discloses a modular architecture
J Biol Chem
(2004) - et al.
CHDL: a cadherin-like domain in Proteobacteria and Cyanobacteria
FEMS Microbiol Lett
(2005) - et al.
The fat-like gene of Drosophila is the true orthologue of vertebrate fat cadherins and is involved in the formation of tubular organs
J Biol Chem
(2004) Armadillo repeat proteins: beyond the animal kingdom
Trends Cell Biol
(2003)- et al.
Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse
Curr Biol
(2003) - et al.
Insights into the low adhesive capacity of human T-cadherin from the NMR structure of its N-terminal extracellular domain
J Biol Chem
(2008) - et al.
Cadherin-like domains in alpha-dystroglycan, alpha/epsilon-sarcoglycan and yeast and bacterial proteins
Curr Biol
(2002) - et al.
Mu-protocadherin, a novel developmentally regulated protocadherin with mucin-like domains
J Biol Chem
(2000)
Desmosomes: new perspectives on a classic
J Invest Dermatol
Cadherin superfamily proteins in Caenorhabditis elegans and Drosophila melanogaster
J Mol Biol
The calsyntenins--a family of postsynaptic membrane proteins with distinct neuronal expression patterns
Mol Cell Neurosci
Identification of new human cadherin genes using a combination of protein motif search and gene finding methods
J Mol Biol
P120-catenin is a novel desmoglein 3 interacting partner: identification of the p120-catenin association site of desmoglein 3
Exp Cell Res
The 2R hypothesis: an update
Curr Opin Immunol
The unicellular ancestry of animal development
Dev Cell
Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET
J Biol Chem
Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex
Neuron
Structure of the cadherin-related neuronal receptor/protocadherin-alpha first extracellular cadherin domain reveals diversity across cadherin families
J Biol Chem
Protocadherin family: diversity, structure, and function
Curr Opin Cell Biol
Interaction with protocadherin-gamma regulates the cell surface expression of protocadherin-alpha
J Biol Chem
Cadherin-related neuronal receptor 1 (CNR1) has cell adhesion activity with beta1 integrin mediated through the RGD site of CNR1
Exp Cell Res
A comprehensive survey of cadherin superfamily gene expression patterns in Ciona intestinalis
Gene Exp Patterns
Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members
J Mol Biol
Nonchordate classic cadherins have a structurally and functionally unique domain that is absent from chordate classic cadherins
Dev Biol
Timing and mechanism of ancient vertebrate genome duplications – the adventure of a hypothesis
Trends Genet
Selectins: critical mediators of leukocyte recruitment
Semin Immunol
Type II cadherin ectodomain structures: implications for classical cadherin specificity
Cell
PCNS: a novel protocadherin required for cranial neural crest migration and somite morphogenesis in Xenopus
Dev Biol
T-cadherin, a novel cadherin cell adhesion molecule in the nervous system lacks the conserved cytoplasmic region
Neuron
Genomic organization and transcripts of the zebrafish Protocadherin genes
Gene
Structure–function analysis of cell adhesion by neural (N-) cadherin
Neuron
Diverse functions of p120ctn in tumors
Biochim Biophys Acta Mol Cell Res
Calsyntenin-1, a proteolytically processed postsynaptic membrane protein with a cytoplasmic calcium-binding domain
Mol Cell Neurosci
The echinoderm adhesome
Dev Biol
Genomic sequence analysis of the mouse desmoglein cluster reveals evidence for six distinct genes: characterization of mouse DSG4, DSG5, and DSG6
J Invest Dermatol
Identification and characterization of three members of a novel subclass of protocadherins
Genomics
The premetazoan ancestry of cadherins
Science
The cadherin superfamily: diversity in form and function
J Cell Sci
The deep roots of eukaryotes
Science
C-cadherin ectodomain structure and implications for cell adhesion mechanisms
Science
Two separate molecular systems, Dachsous/Fat and Starry night/Frizzled, act independently to confer planar cell polarity
Development
Paraxial protocadherin mediates cell sorting and tissue morphogenesis by regulating C-cadherin adhesion activity
J Cell Biol
Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype
Mol Cell Biol
Dachsous encodes a member of the cadherin superfamily that controls imaginal disc morphogenesis in Drosophila
Genes Dev
Armadillo-related proteins promote lateral root development in Arabidopsis
Proc Natl Acad Sci U S A
WebLogo: a sequence logo generator
Genome Res
Broad phylogenomic sampling improves resolution of the animal tree of life
Nature
Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells
J Cell Sci
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