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Evolution and diversity of cadherins and catenins
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Evolution and diversity of cadherins and catenins Ismail Sahin Gula,b,1, Paco Hulpiaua,b,1, Yvan Saeysa,c, Frans van Roya,b, a b c
⁎
Center for Inflammation Research, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Department of Internal Medicine, Ghent University, Ghent, Belgium
A R T I C L E I N F O
A BS T RAC T
Keywords: Cadherin superfamily Armadillo superfamily Catenins Molecular evolution Cell adhesion Protocadherins α-catenin
Cadherin genes encode a superfamily of conserved transmembrane proteins that share an adhesive ectodomain composed of tandem cadherin repeats. More than 100 human cadherin superfamily members have been identified, which can be classified into three families: major cadherins, protocadherins and cadherin-related proteins. These superfamily members are involved in diverse fundamental cellular processes including cell-cell adhesion, morphogenesis, cell recognition and signaling. Epithelial cadherin (E-cadherin) is the founding cadherin family member. Its cytoplasmic tail interacts with the armadillo catenins, p120 and β-catenin. Further, α-catenin links the cadherin/armadillo catenin complex to the actin filament network. Even genomes of ancestral metazoan species such as cnidarians and placozoans encode a limited number of distinct cadherins and catenins, emphasizing the conservation and functional importance of these gene families. Moreover, a large expansion of the cadherin and catenin families coincides with the emergence of vertebrates and reflects a major functional diversification in higher metazoans. Here, we revisit and review the functions, phylogenetic classifications and co-evolution of the cadherin and catenin protein families.
1. Metazoan evolution and diversity of cadherins 1.1. Classification and adhesion modes of cadherin superfamily members The cadherin superfamily comprises calcium-dependent membrane proteins involved in cell-cell adhesion and cell-cell recognition. Each protein possesses at least two consecutive extracellular cadherin (EC) repeats and belongs to one of three families: the cadherin (CDH) family proper, the protocadherin (PCDH) family or the cadherin-related (CDHR) family [1]. The human reference genome encodes 114 protein encoding genes, which can be classified into one of these three families on the basis of their evolutionary history and their functional and structural features. Considering their respective sequence homologies each family can be further subdivided into smaller subfamilies with more closely related members (Table 1). The founding member of the superfamily is E-cadherin or cadherin 1 (CDH1), which is one of the 32 members of the major cadherin family found in humans. Structural studies showed a similar interaction mode in all type-I classical cadherins, in cadherin 26 (CDH26) and in desmosomal cadherins (Fig. 1A). The N-terminal cadherin repeat
(EC1) forms a homophilic interaction in trans with the same cadherin type on the opposing cell surface. A conserved tryptophan residue (Trp2) in the so-called adhesion arm is inserted in the hydrophobic pocket of the adhesion partner forming a strand-swap dimer [2]. The second cadherin repeat (EC2) interacts in cis with the EC1 of the neighboring cadherin on the same cell surface. Type-II classical cadherins use the same homophilic interaction mechanism but here two tryptophan residues (Trp2 and Trp4) are inserted into a larger hydrophobic pocket [3]. 7D cadherins and the CELSR cadherins have more than five EC repeats [1]. Their exact interaction mechanism is currently unknown. CELSR cadherins do not have a conserved Trp like the other members of the cadherin family and will therefore use another interaction mechanism. Interestingly, the 7D cadherin CDH17 and E-cadherin (CDH1) can form heterophilic trans interactions with each other [4]. 7D cadherins contain seven EC repeats and have one conserved Trp in their third EC repeat (EC3), which could form the typical strand-swap dimer with the EC1 from classical cadherins having five EC repeats. Except for these 7D cadherins, the three CELSR cadherins and CDH13, all other members in the major cadherin family have conserved cytoplasmic domains, which can interact with armadillo catenins as described in some detail below.
⁎ Correspondence to: Department of Biomedical Molecular Biology & Center for Inflammation Research, Ghent University & VIB, FSVM Building, Technologiepark 927, B-9052 Ghent, Belgium. E-mail address: [email protected] (F. van Roy). 1 Contributed equally.
http://dx.doi.org/10.1016/j.yexcr.2017.03.001 Received 16 January 2017; Received in revised form 27 February 2017; Accepted 1 March 2017 0014-4827/ © 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Gul, I.S., Experimental Cell Research (2017), http://dx.doi.org/10.1016/j.yexcr.2017.03.001
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Table 1 Classification and official nomenclature of the 114 human cadherin protein encoding genes. Family
Subfamily
Official gene names (HGNC symbol, common alias)
Major cadherins (CDH) 32 members
Type I classical cadherins
cadherin 1 (CDH1, E-cadherin), cadherin 2 (CDH2, N-cadherin), cadherin 3 (CDH3, P-cadherin), cadherin 4 (CDH4, R-cadherin), cadherin 15 (CDH15, M-cadherin) cadherin 5 (CDH5, VE-cadherin), cadherin 6 (CDH6, K-cadherin), cadherin 7 (CDH7), cadherin 8 (CDH8), cadherin 9 (CDH9, T1-cadherin), cadherin 10 (CDH10, T2-cadherin), cadherin 11 (CDH11, OBcadherin), cadherin 12 (CDH12, N-cadherin 2), cadherin 18 (CDH18), cadherin 19 (CDH19), cadherin 20 (CDH20), cadherin 22 (CDH22), cadherin 24 (CDH24) cadherin 16 (CDH16, Ksp-cadherin), cadherin 17 (CDH17, LI-cadherin) desmocollin 1 (DSC1), desmocollin 2 (DSC2), desmocollin 3 (DSC3), desmoglein 1 (DSG1), desmoglein 2 (DSG2), desmoglein 3 (DSG3), desmoglein 4 (DSG4) cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1), cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) cadherin 13 (CDH13, H-cadherin), cadherin 26 (CDH26)
Type II classical cadherins
7D cadherins Desmosomal cadherins Flamingo or CELSR cadherins – Protocadherins (PCDH) 65 members
Clustered protocadherins
Non-clustered protocadherins
Cadherin-related (CDHR) 17 members
–
Dachsous FAT Calsyntenins
protocadherin alpha cluster (PCDHA@: PCDHAC1, PCDHAC2, PCDHA1 up to PCDHA14), protocadherin beta cluster (PCDHB@: PCDHB1 up to PCDHB16), protocadherin gamma cluster (PCDHG@: PCDHGA1 up to PCDHGA12, PCDHGB1 up to PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5) protocadherin 1 (PCDH1), protocadherin 7 (PCDH7), protocadherin 8 (PCDH8), protocadherin 9 (PCDH9), protocadherin 10 (PCDH10), protocadherin 11 X-linked and Y-linked (PCDH11X and PCDH11Y), protocadherin 12 (PCDH12), protocadherin 17 (PCDH17), protocadherin 18 (PCDH18), protocadherin 19 (PCDH19), protocadherin 20 (PCDH20) cadherin related family member 1 (CDHR1, PCDH21), cadherin related family member 2 (CDHR2, PCDH24), cadherin related family member 3 (CDHR3, CDH28), cadherin related family member 4 (CDHR4, CDH29), cadherin related family member 5 (CDHR5, MU-PCDH), protocadherin related 15 (PCDH15, CDHR15), ret proto-oncogene (RET, CDHR16), cadherin related 23 (CDH23, CDHR23) dachsous cadherin-related 1 (DCHS1, CDHR6), dachsous cadherin-related 2 (DCHS2, CDHR7) FAT atypical cadherin 1 (FAT1, CDHR8), FAT atypical cadherin 2 (FAT2, CDHR9), FAT atypical cadherin 3 (FAT3, CDHR10), FAT atypical cadherin 4 (FAT4, CDHR11) calsyntenin 1 (CLSTN1, CDHR12), calsyntenin 2 (CLSTN2, CDHR13), calsyntenin 3 (CLSTN3, CDHR14)
Official human gene nomenclature (HGNC) symbols are in bold and underlined. Human calcium-dependent membrane proteins with at least two consecutive extracellular cadherin (EC) repeats can be classified into three large families (first column) based on phylogenetic analysis Ref. [1]. The family subtrees in such evolutionary analysis reveal several subfamilies (second column). Members of the subfamilies (third column) have similar functional and structural features as described in the main text.
actions between DCHS1 with 27 EC repeats and FAT4 with 34 EC repeats regulate planar cell polarity and cell proliferation [9]. Classical cadherins are typically found in adherens junctions (AJs). To fit in a 30- to 45-nm intercellular junction, only about double the size of AJs, the giant cadherins were shown to self-bend at certain EC-EC linkers where the typical calcium binding amino acids (AAs) are not conserved [9] (Fig. 1D). Two other cadherin-related proteins PCDH15 (CDHR15) and CDH23 (CDHR23) are found at tip links of stereocilia in the inner ear and are part of the hair-cell transduction machinery [10]. Note that although their official gene symbols refer to protocadherins and classical cadherins, PCDH15 (CDHR15) with 11 EC repeats and CDH23 (CDHR23) with 27 EC repeats are not a protocadherin and not a cadherin, respectively [1]. They form specific heterophilic trans interaction complexes by means of an extended handshake of the EC1EC2 repeats between a PCDH15 cis dimer on the one hand and a CDH23 cis dimer on the other hand (Fig. 1E). Lastly, CDHR2 (PCDH24) and CDHR5 (MU-PCDH) can also heterophilically transinteract to form intermicrovillar adhesion links between adjacent microvilli in the intestinal brush border [11]. Like PCDH15 and CDH23, CDHR2 with nine EC repeats and CDHR5 with four EC repeats have different domain compositions and phylogenetic positions in the superfamily than the protocadherins, but both are often still incorrectly called a protocadherin (PCDH24 and MU-PCDH) rather than a cadherin-related protein.
Protocadherins (PCDH) form in vertebrates the largest cadherin family composed of two subfamilies: clustered and non-clustered protocadherins (Table 1). They play a crucial role in the vertebrate nervous system by generating cell surface diversity and specificity, in that way determining the cellular identity of individual neurons [5]. Mammals have three clusters of protocadherin genes, α-PCDH, βPCDH and γ-PCDH, organized consecutively on the genome. At the cell surface promiscuous cis dimer formation occurs between the membrane-proximal EC repeats (EC6) (Fig. 1B). Two models have been proposed for explaining how such dimeric recognition units can engage in trans interface binding [6]. Tetramers can be formed by head-to-tail EC1 to EC4 trans interactions of the cis dimers. In a second model cis dimers bind two dimeric recognition units on the opposing cell surface and by repeating this a zipper-like assembly can be established (Fig. 1B). The genes of the non-clustered protocadherin subfamily, also called delta-protocadherins (δ-PCDH), are largely dispersed in the genome. Part of the δ-PCDH proteins (the δ2-PCDHs) have six EC repeats like the clustered protocadherins, others (the δ1-PCDHs) possess seven EC repeats. The structure of zebrafish PCDH19, a δ2PCDH, revealed a “forearm handshake” adhesion involving EC1 tot EC4 domains resulting in a fully overlapping antiparallel, homophilic trans dimer (Fig. 1C, [7]). This binding mechanism is similar to the trans interaction mode of clustered protocadherins. Other non-clustered protocadherins are expected to use the same adhesive interface. The cadherin-related family (CDHR) gathers the most diverse members. The calsyntenins, involved in learning and memory formation, have only two EC repeats, which are together able to mediate either homophilic or heterophilic adhesive interactions [8]. It is currently unclear if their primary activity is cell-cell adhesion. Other functions such as secreted ligands or transport chaperones have been suggested. The Dachsous (DCHS1, DCHS2) and FAT (FAT1, −2,−3 and FAT4) cadherins are among the longest cadherins. Heterophilic inter-
1.2. Evolution of the cadherin superfamily The first proteins able to mediate calcium-dependent cell-cell adhesion by means of at least two EC repeats and by this definition belonging to the cadherin superfamily, appeared in the last common ancestor of animals more than 600 million years ago. Only a few
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Fig. 1. Cell-cell adhesion mechanisms in the cadherin superfamily. Each extracellular cadherin (EC) repeat is represented as an ellips being part of cadherin ectodomains in the gap between opposing cell surfaces and numbered starting from the first N-terminal repeat (EC1). Transmembrane regions (TM) are show on top of gray bars. (A) Classical and desmosomal cadherins with 5 EC repeats engage homophilic EC1-EC1 interactions between molecules on opposing cell surfaces (trans), as well as intramolecular interactions between EC1-EC2 repeats of molecules on the same cell surface (cis). (B) Two interaction modes of clustered protocadherins. EC6 repeats are important for cis interactions and domains comprising EC1 to EC4 repeats for trans interactions. (C) Interaction mechanism of non-clustered protocadherins based on the structure of PCDH19. (D) Interaction of the cadherin-related molecules FAT4 and DCHS1 as observed by electron microscopy. (E) Interaction of EC1-EC2 repeats of a PCDH15 (CDHR15) dimer with EC1-EC2 repeats of a CDH23 (CDHR23) dimer. See text for references.
of CELSR, FAT and FAT-like cadherins, suggests that these ancient cadherins emerged as paralogs in the most ancestral animals. Since then, they have been evolving by progressive loss of N-terminal EC repeats in combination with loss of membrane-proximal domains in the ectodomain [12]. The type-III classical cadherin can still be found in e.g. insects, roundworms, fishes and birds, but has been lost in mammals. Instead, the classical cadherin family has greatly expanded in vertebrates with over 30 genes in mammals (Fig. 2). Remarkably, the cytoplasmic domains of these cadherins, which are known to interact with armadillo catenins, have remained highly conserved throughout animal evolution.
representative members of the different cadherin families are found in non-bilaterian, basal animals such as cnidarians e.g. the sea anemone Nematostella and placozoans e.g. Trichoplax [12]. This basic cadherin set is highly conserved, found in nearly all animals and consists of a classical cadherin (CDH family), a nonclassical flamingo/CELSR cadherin (CDH family) and several cadherin-related members such as FAT, FAT-like and DCHS (CDHR family) (Fig. 2). The ancestral classical cadherin (type III) was much longer than the classical cadherins (type I and II) found in vertebrates. The presence of multiple epidermal growth factor like (EGF-like) and laminin G domains in the extracellular region, similar to the domain composition
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Fig. 2. Metazoan evolution of cadherin and catenin superfamilies. (Left) Cladogram showing the evolutionary relations among the organisms analyzed: Trichoplax adhaerens for Placozoa; Nematostella vectensis for Cnidaria; Caenorhabditis elegans and Drosophila melanogaster for Ecdysozoa; Aplysia californica for Lophotrochozoa; Ciona intestinalis, Branchiostoma floridae and Strongylocentrotus purpuratus for other deuterostomes; Gallus gallus, Xenopus tropicalis and Danio rerio for other vertebrates; Homo sapiens and Mus musculus for Mammalia. (Right) Number of cadherin family and catenin family members throughout metazoan evolution. Dashed box represents the loss of protocadherins in Ecdysozoans. + indicates duplications of family members in some species in the lineage.
(also called γ-catenin or junction plakoglobin/JUP). The largest subfamily, δ-catenins, has seven members and can be divided into two branches, a CTNND core branch (or p120 branch) and a plakophilin branch. The CTNND core branch has four members: p120 catenin (δ1catenin or CTNND1), ARVCF (armadillo repeat gene deleted in velocardiofacial syndrome), δ-catenin (δ2-catenin or CTNND2) and p0071, also known as plakophilin-4 (PKP4). Finally, the plakophilin branch consists of plakophilin-1 (PKP1), −2 (PKP2) and −3 (PKP3) [15]. While the α-catenin subfamily can be recognized by their vinculin homology domains, the β- and δ-catenin subfamily members possess series of armadillo (Arm) repeats.
Protocadherins were not present in the most ancestral animals. A single protocadherin with seven EC repeats has been identified in cnidarians and several other invertebrates. Ecdysozoa including arthropods and nematodes have lost this protocadherin. Interestingly, a massive expansion of the protocadherin family occurred in vertebrates leading to non-clustered protocadherins with seven or six EC repeats and to numerous clustered protocadherins, each with six EC repeats (Fig. 2). The cadherin-related family is the smallest one with mainly long, atypical cadherins of which FAT has evolved in vertebrates to FAT1, FAT2 and FAT3. Also the exceptionally short calsyntenins expanded to three copies CLSTN1, CLSTN2 and CLSTN3 in vertebrates. Some cadherin-related proteins such as CDHR2 (PCDH24), CDHR5 (MUPCDH), CDHR15 (PCDH15) and CDHR23 (CDH23) appeared only later during animal evolution and their co-evolution was probably due to their mutual heterophilic interactions (see above and Fig. 1E). Other, deviating cadherin-related proteins are mainly found in basal, nonbilaterian animals and appear to be rather lineage-specific. They have been lost in more recently evolved vertebrate and invertebrate animals [12].
2.2. Functions and evolution of β-catenin subfamily members Arm repeats share similar tandem copies of sequence motifs, which are composed of about 42 AAs and form a conserved three-dimensional structure. They were first identified in the Drosophila segment polarity protein Armadillo involved in signal transduction through wingless [16]. Drosophila Armadillo gave the name for this superfamily and is the homolog of mammalian β-catenin. The same motifs were then recognized in the vertebrate homologs of other adherens junctional proteins, such as plakoglobin and p120-catenin [17,18]. The first armadillo structure characterized was the armadillo domain of murine β-catenin, which comprises 12 Arm repeats with each repeat being composed of three helices [19]. Since then the structures and functions of β-catenin have been studied extensively and more than ten crystal structures and 20 interaction partners of β-catenin have meanwhile been reported (reviewed in [20]). Besides its essential role in cell-cell adhesion, β-catenin is one of the key regulators of the canonical Wnt signaling pathway (also referred to as Wnt/β-catenin pathway), an important cascade that regulates cell fate during development. All known extant animals can be divided into five clades: Bilateria, Cnidaria, Placozoa, Ctenophora (comb jellies) and Porifera (sponges). Evolutionary studies on β-catenin by homology searches and phylogenetic analyses revealed that it was present far back in early branching metazoans [15,21] (Fig. 2). A single copy of β-catenin can be found in non-bilaterian animals, such as cnidarian Nematostella vectensis, placozoan Trichoplax adhaerens, ctenophoran Mnemiopsis leidyi and poriferan Amphimedon queenslandica [22]. In line with this, the genomes of these organisms encode also the major components of canonical Wnt signaling, including Frizzled, LRP5/6, Dishevelled and TCF/LEF [23]. While the central armadillo domain of β-catenin, composed of 12 Arm repeats, shows strong sequence conservation throughout metazoan evolution, the terminal domains are more
2. Metazoan evolution and diversity of catenins 2.1. Structures and classification of catenin family members In 1989, Ozawa and colleagues reported an immunoprecipitation experiment where they pulled down uvomorulin (later renamed as Ecadherin) in complex with three proteins of, respectively, 102, 88 and 80 kDa long, and named them as α-, β- and γ-catenin (derived from catena, the Latin word for chain) [13]. Catenins turned out to be key components of the cadherin-based cell adhesion mode. The single-pass transmembrane protein E-cadherin engages in Ca2+-dependent homophilic interactions via their extracellular regions composed of EC domains. At the cytoplasmic side, the tail of E-cadherin forms a complex with armadillo catenins (p120- and β-catenin) and indirectly with α-catenin, which is homologous to vinculin. The latter interaction occurs through β-catenin and connects the E-cadherin cytoplasmic tail with the underlying actin cytoskeleton [14]. This complex is also referred to as the E-cadherin/β-catenin/α-catenin complex or CCC. Based on their sequence homology, the catenin family members can be divided into three subfamilies named after representative members (Fig. 2). The α-catenin subfamily consists of αE-, αN- and αT-catenins, where E stands for epithelial, N for neural, and T for testis, respectively. The β-catenin subfamily comprises β-catenin and plakoglobin 4
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catenin or plakoglobin, it is not clear from which p120 branch member they originated at the origin of vertebrates [21].
divergent and not likely to form a stable folded structure. A recent study, investigating junctional proteins in the non-bilaterian organism N. vectensis, revealed that N. vectensis β-catenin was able to interact with the classical cadherins of N. vectensis, NvCDH1 and NvCDH2, and able to form a ternary CCC [24], indicating the conservation of a cell adhesion function of β-catenin in organisms predating Bilateria. Ancestral β-catenin has gone through several lineage-specific duplications in particular bilaterian lineages. Remarkably, the Caenorhabditis elegans genome encodes four distinct β-catenin orthologs: Hmp-2, Bar-1, Wrm-1 and Sys-1 [25,26]. While a single mammalian β-catenin exerts dual functions in signaling and cell adhesion, in C. elegans the signaling and cell adhesion pools of βcatenin are separate players. For instance, yeast-two hybrid and immunoprecipitation experiments showed that Hmp-2 is the only βcatenin paralog that interacts with the E-cadherin ortholog of C. elegans, Hmr-1 [25]. Further structural and biochemical analysis on the Hmr-1 and Hmp-2 proteins confirmed molecular complex formation between them [27]. This lineage-specific evolution, which resulted in four β-catenin paralogs in C. elegans, provides an opportunity to study the adhesion and signaling roles of β-catenin separately. In vertebrates, β-catenin underwent a duplication event what gave rise to plakoglobin. Similar to β-catenin, plakoglobin has 12 Arm repeats and functions in the adherens junctions. Contrary to β-catenin, plakoglobin is not involved in TCF/LEF-dependent transcriptional activation [28]. However, plakoglobin is essential for the formation of desmosomes as it forms a complex with the desmosomal cadherins desmoglein and desmocollin, plakophilins and desmoplakin [29]. βcatenin is not a structural constituent of desmosomes and does not interact strongly with desmosomal cadherins [30].
3. Non-metazoan origin and diversity of cadherins and catenins
2.3. Functions and evolution of δ-catenin subfamily members
3.1. Cadherin-like molecules in non-metazoans
When compared with the 12 tandem Arm repeats of β-catenin, all seven δ-catenin members have only nine Arm repeats [31,32]. Moreover, the Arm repeats of the δ-catenin members are interrupted by an insert of about 60 AA, situated between the 5th and the 6th Arm repeat. In vertebrates, p120 catenin is a structural component of the CCC, but in addition, it prevents endocytosis of classical cadherins by interacting with their cytoplasmic juxtamembrane domains at a site, which overlaps with the endocytic dileucine motif. By masking this motif, vertebrate p120 catenin prevents the interaction between the cytoplasmic tail of classical cadherins on the one hand and Presenilin-1 and Hakai on the other hand (reviewed in [33]). Similar to p120 catenin, the other CTNND core branch members, Ctnnd2, Arcvf and p0071, are involved in the regulation of cadherin stability at cell–cell junctions (reviewed in [34]). Moreover, all four members of this branch participate in actin cytoskeleton remodeling by regulating Rho family GTPases (reviewed in [35]). Except for the sea squirt Ciona intestinalis and sea anemone Nematostella vectensis, where two copies of δ-catenin members are found, all invertebrate animals have a single ancestral δ-catenin (Fig. 2). Our previous comparative sequence analyses on δ-catenin subfamily members revealed that the first duplication event has occurred at the origin of vertebrates. In line with this, the two copies of δ-catenins from the tunicate C. intestinalis, CiCtnnd-A and CiCtnndB, form separate clades with vertebrate Ctnnd1/Arvcf and Ctnnd2/ Pkp4 proteins [22]. Plakophilins were identified as desmosomal plaque proteins that are essential for the stabilization and the formation of desmosomes via their association with desmosomal cadherins (reviewed in [36]). Plakophilin encoding genes are located on different chromosomes but these genes show exon/intron boundaries that are at almost identical positions of the respectively encoded AA sequences. This suggests that they originated from a common ancestor quite recently in evolution. Although plakophilins show higher similarity to the p120 branch members than to β-
Some form of cell-cell adhesion was required to evolve from unicellularity to the first multicellular animals (Metazoa). For cadherins to play a role in this, cadherin-like molecules had to be present before the appearance of the first animals. It was nonetheless some surprise that researchers found cadherin-like genes in choanoflagellates, the closest single-celled relatives of animals [41]. Meanwhile, cadherin-like genes have been reported in several other non-metazoan species [42–45]. However, currently there is neither functional nor structural evidence that these cadherin-like molecules act as calciumdependent cell adhesion molecules as extensively documented in animal cell-cell adhesion. Indeed, these non-metazoan molecules needed to be classified in a separate cadherin-like (CDHL) family (not to be confused with the cadherin-related or CDHR family). For instance, the cadherin-like domains found in Proteobacteria and Cyanobacteria do not have the typical conserved calcium-binding motifs LDRE and DxNDN found in the whole cadherin superfamily [43]. Structure determination of the predicted cadherin-like domain in α-dystroglycans [42] revealed an Ig-like domain different from the typical cadherin fold [46]. In conclusion, to determine if some of these cadherin-like (CDHL) proteins truly belong to the cadherin superfamily, additional phylogenetic and structural analyses are required to elucidate whether they share any functional or structural characteristics with members of the three established cadherin families, cadherins, protocadherins and cadherin-related proteins.
2.4. Functions and evolution of α-catenin subfamily members α-Catenin subfamily members function as a bridge between the actin bundles and the E-cadherin/p120 catenin/β-catenin heterotrimer. While the N-terminal domain of α-catenin binds this of βcatenin, the C-terminal part interacts at the same time with the actin filaments [37]. In addition, α-catenin homodimers can also bind actin filaments and regulate the actin cytoskeleton by suppressing Arp2/3mediated actin polymerization [38,39]. Both CCC-bound monomeric αcatenin and α-catenin homodimers are required for stable cell-cell adhesion [40]. In particular αE-catenin has been studied extensively and this is also the most widely expressed family member. αT-catenin expression is largely restricted to cardiomyocytes and αN-catenin is a major constituent of intercellular junctions in the neural system. αN- and αE-catenins show more than 80% sequence identity, whereas αTcatenin is more distantly related to these two α-catenins. Similar to the evolutionary history of the two armadillo catenin subfamilies, a single α-catenin ortholog can be found in early diverging metazoan species (Fig. 2). Previous phylogenetic analyses identified αN-catenin as the ancestor of all α-catenins. In vertebrates, αN-catenin gave rise to αEcatenin, while the most recently evolved member, αT-catenin, arose as a result of an amniote-specific gene duplication event [15,21].
3.2. Catenin-like molecules in non-metazoans Sequence searches for β-catenin proteins revealed that no β-catenin homolog can be found in choanoflagellates Monosiga brevicollis and Salpingoeca rosetta, which are the closest known relatives of metazoans [21]. However, in other non-metazoan species β-catenin like proteins have been reported, such as unicellular yeast Saccharomyces cerevisiae Vac8p and slime mold Dictyostelium discoideum Aardvark which share 22% and 18% identity to mammalian β5
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catenin, respectively. Although D. discoideum lacks an ortholog of a classical cadherin, its β-catenin ortholog Aardvark is able to interact with an α-catenin-like gene product, which is essential for the formation of a particular polarized epithelium [47]. Although the catenin family members share the same core name ‘catenin’, the three subfamilies, α-, β- and δ-, have different evolutionary origins. Our recent study on the evolution of the Arm repeat superfamily revealed that β- and δ-catenins are not evolutionarily related to each other and have evolved from different premetazoan ancestors [22]. Bayesian phylogeny suggests that while the δ-catenins and armadillo formins share a common ancestral origin, β-catenin and the related plakoglobin are related to an uncharacterized protein called Armadillo repeat-containing protein 6 (Armc6) [22]. Although biochemical analyses suggest that the α-catenin protein from Dictyostelium discoideum functions like metazoan α-catenin [47], phylogenetic analysis on the vinculin gene family positions this D. discoideum α-catenin rather as an ortholog of vinculin [48]. More research on non-metazoan organisms, such as Choanoflagellida and Capsaspora, is required to explore the function and evolutionary origin of metazoan and non-metazoan α-catenin gene family members. Acknowledgements We thank our colleagues for helpful discussions. This work was supported by the Research Foundation – Flanders (FWO-Vlaanderen, Award G.0320.11N), the Belgian Science Policy (Interuniversity Attraction Poles – Award IAP7/07), and the Special Research Fund of Ghent University (Award BOF 01J14211). References [1] P. Hulpiau, F. van Roy, Molecular evolution of the cadherin superfamily, Int J. Biochem. Cell Biol. 41 (2) (2009) 349–369 (doi:S1357-2725)(08)(00404-4 )(pii) (10.1016/j.biocel.2008.09.027). [2] O.J. Harrison, X. Jin, S. Hong, F. Bahna, G. Ahlsen, J. Brasch, Y. Wu, J. Vendome, K. Felsovalyi, C.M. Hampton, R.B. Troyanovsky, A. Ben-Shaul, J. Frank, S.M. Troyanovsky, L. Shapiro, B. Honig, The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins, Structure 19 (2) (2011) 244–256 (doi:S0969-2126)(11)(00003-7 )(pii)(10.1016/j.str.2010.11.016). [3] S.D. Patel, C. Ciatto, C.P. Chen, F. Bahna, M. Rajebhosale, N. Arkus, I. Schieren, T.M. Jessell, B. Honig, S.R. Price, L. Shapiro, Type II cadherin ectodomain structures: implications for classical cadherin specificity, Cell 124 (6) (2006) 1255–1268. [4] W. Baumgartner, M.W. Wendeler, A. Weth, R. Koob, D. Drenckhahn, R. Gessner, Heterotypic trans-interaction of LI- and E-cadherin and their localization in plasmalemmal microdomains, J. Mol. Biol. 378 (1) (2008) 44–54. [5] T. Yagi, Genetic basis of neuronal individuality in the mammalian brain, J. Neurogenet. 27 (3) (2013) 97–105. http://dx.doi.org/10.3109/ 01677063.2013.801969. [6] K.M. Goodman, R. Rubinstein, C.A. Thu, S. Mannepalli, F. Bahna, G. Ahlsen, C. Rittenhouse, T. Maniatis, B. Honig, L. Shapiro, Gamma-protocadherin structural diversity and functional implications, Elife (2016) 5. http://dx.doi.org/10.7554/ eLife.20930. [7] S.R. Cooper, J.D. Jontes, M. Sotomayor, Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy, Elife (2016) 5. http:// dx.doi.org/10.7554/eLife.18529. [8] H. Ortiz-Medina, M.R. Emond, J.D. Jontes, Zebrafish calsyntenins mediate homophilic adhesion through their amino-terminal cadherin repeats, Neuroscience 286 (2015) 87–96. http://dx.doi.org/10.1016/j.neuroscience.2014.11.030. [9] Y. Tsukasaki, N. Miyazaki, A. Matsumoto, S. Nagae, S. Yonemura, T. Tanoue, K. Iwasaki, M. Takeichi, Giant cadherins fat and dachsous self-bend to organize properly spaced intercellular junctions, Proc. Natl. Acad. Sci. USA 111 (45) (2014) 16011–16016. http://dx.doi.org/10.1073/pnas.1418990111. [10] R. Araya-Secchi, B.L. Neel, M. Sotomayor, An elastic element in the protocadherin15 tip link of the inner ear, Nat. Commun. 7 (2016) 13458. http://dx.doi.org/ 10.1038/ncomms13458. [11] S.W. Crawley, M.S. Mooseker, M.J. Tyska, Shaping the intestinal brush border, J. Cell Biol. 207 (4) (2014) 441–451. http://dx.doi.org/10.1083/jcb.201407015. [12] P. Hulpiau, F. Van Roy, New insights into the evolution of metazoan cadherins, Mol. Biol. Evol. 28 (1) (2011) 647–657 (doi:msq233 )(pii)(10.1093/molbev/ msq233). [13] M. Ozawa, H. Baribault, R. Kemler, The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species, EMBO J. 8 (6) (1989) 1711–1717. [14] M. Takeichi, Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling, Nat. Rev. Mol. Cell Biol. 15 (6) (2014) 397–410. http://dx.doi.org/
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Experimental Cell Research journal homepage: www.elsevier.com/locate/yexcr
Evolution and diversity of cadherins and catenins Ismail Sahin Gula,b,1, Paco Hulpiaua,b,1, Yvan Saeysa,c, Frans van Roya,b, a b c
⁎
Center for Inflammation Research, VIB, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium Department of Internal Medicine, Ghent University, Ghent, Belgium
A R T I C L E I N F O
A BS T RAC T
Keywords: Cadherin superfamily Armadillo superfamily Catenins Molecular evolution Cell adhesion Protocadherins α-catenin
Cadherin genes encode a superfamily of conserved transmembrane proteins that share an adhesive ectodomain composed of tandem cadherin repeats. More than 100 human cadherin superfamily members have been identified, which can be classified into three families: major cadherins, protocadherins and cadherin-related proteins. These superfamily members are involved in diverse fundamental cellular processes including cell-cell adhesion, morphogenesis, cell recognition and signaling. Epithelial cadherin (E-cadherin) is the founding cadherin family member. Its cytoplasmic tail interacts with the armadillo catenins, p120 and β-catenin. Further, α-catenin links the cadherin/armadillo catenin complex to the actin filament network. Even genomes of ancestral metazoan species such as cnidarians and placozoans encode a limited number of distinct cadherins and catenins, emphasizing the conservation and functional importance of these gene families. Moreover, a large expansion of the cadherin and catenin families coincides with the emergence of vertebrates and reflects a major functional diversification in higher metazoans. Here, we revisit and review the functions, phylogenetic classifications and co-evolution of the cadherin and catenin protein families.
1. Metazoan evolution and diversity of cadherins 1.1. Classification and adhesion modes of cadherin superfamily members The cadherin superfamily comprises calcium-dependent membrane proteins involved in cell-cell adhesion and cell-cell recognition. Each protein possesses at least two consecutive extracellular cadherin (EC) repeats and belongs to one of three families: the cadherin (CDH) family proper, the protocadherin (PCDH) family or the cadherin-related (CDHR) family [1]. The human reference genome encodes 114 protein encoding genes, which can be classified into one of these three families on the basis of their evolutionary history and their functional and structural features. Considering their respective sequence homologies each family can be further subdivided into smaller subfamilies with more closely related members (Table 1). The founding member of the superfamily is E-cadherin or cadherin 1 (CDH1), which is one of the 32 members of the major cadherin family found in humans. Structural studies showed a similar interaction mode in all type-I classical cadherins, in cadherin 26 (CDH26) and in desmosomal cadherins (Fig. 1A). The N-terminal cadherin repeat
(EC1) forms a homophilic interaction in trans with the same cadherin type on the opposing cell surface. A conserved tryptophan residue (Trp2) in the so-called adhesion arm is inserted in the hydrophobic pocket of the adhesion partner forming a strand-swap dimer [2]. The second cadherin repeat (EC2) interacts in cis with the EC1 of the neighboring cadherin on the same cell surface. Type-II classical cadherins use the same homophilic interaction mechanism but here two tryptophan residues (Trp2 and Trp4) are inserted into a larger hydrophobic pocket [3]. 7D cadherins and the CELSR cadherins have more than five EC repeats [1]. Their exact interaction mechanism is currently unknown. CELSR cadherins do not have a conserved Trp like the other members of the cadherin family and will therefore use another interaction mechanism. Interestingly, the 7D cadherin CDH17 and E-cadherin (CDH1) can form heterophilic trans interactions with each other [4]. 7D cadherins contain seven EC repeats and have one conserved Trp in their third EC repeat (EC3), which could form the typical strand-swap dimer with the EC1 from classical cadherins having five EC repeats. Except for these 7D cadherins, the three CELSR cadherins and CDH13, all other members in the major cadherin family have conserved cytoplasmic domains, which can interact with armadillo catenins as described in some detail below.
⁎ Correspondence to: Department of Biomedical Molecular Biology & Center for Inflammation Research, Ghent University & VIB, FSVM Building, Technologiepark 927, B-9052 Ghent, Belgium. E-mail address: [email protected] (F. van Roy). 1 Contributed equally.
http://dx.doi.org/10.1016/j.yexcr.2017.03.001 Received 16 January 2017; Received in revised form 27 February 2017; Accepted 1 March 2017 0014-4827/ © 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Gul, I.S., Experimental Cell Research (2017), http://dx.doi.org/10.1016/j.yexcr.2017.03.001
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Table 1 Classification and official nomenclature of the 114 human cadherin protein encoding genes. Family
Subfamily
Official gene names (HGNC symbol, common alias)
Major cadherins (CDH) 32 members
Type I classical cadherins
cadherin 1 (CDH1, E-cadherin), cadherin 2 (CDH2, N-cadherin), cadherin 3 (CDH3, P-cadherin), cadherin 4 (CDH4, R-cadherin), cadherin 15 (CDH15, M-cadherin) cadherin 5 (CDH5, VE-cadherin), cadherin 6 (CDH6, K-cadherin), cadherin 7 (CDH7), cadherin 8 (CDH8), cadherin 9 (CDH9, T1-cadherin), cadherin 10 (CDH10, T2-cadherin), cadherin 11 (CDH11, OBcadherin), cadherin 12 (CDH12, N-cadherin 2), cadherin 18 (CDH18), cadherin 19 (CDH19), cadherin 20 (CDH20), cadherin 22 (CDH22), cadherin 24 (CDH24) cadherin 16 (CDH16, Ksp-cadherin), cadherin 17 (CDH17, LI-cadherin) desmocollin 1 (DSC1), desmocollin 2 (DSC2), desmocollin 3 (DSC3), desmoglein 1 (DSG1), desmoglein 2 (DSG2), desmoglein 3 (DSG3), desmoglein 4 (DSG4) cadherin EGF LAG seven-pass G-type receptor 1 (CELSR1), cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2), cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) cadherin 13 (CDH13, H-cadherin), cadherin 26 (CDH26)
Type II classical cadherins
7D cadherins Desmosomal cadherins Flamingo or CELSR cadherins – Protocadherins (PCDH) 65 members
Clustered protocadherins
Non-clustered protocadherins
Cadherin-related (CDHR) 17 members
–
Dachsous FAT Calsyntenins
protocadherin alpha cluster (PCDHA@: PCDHAC1, PCDHAC2, PCDHA1 up to PCDHA14), protocadherin beta cluster (PCDHB@: PCDHB1 up to PCDHB16), protocadherin gamma cluster (PCDHG@: PCDHGA1 up to PCDHGA12, PCDHGB1 up to PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5) protocadherin 1 (PCDH1), protocadherin 7 (PCDH7), protocadherin 8 (PCDH8), protocadherin 9 (PCDH9), protocadherin 10 (PCDH10), protocadherin 11 X-linked and Y-linked (PCDH11X and PCDH11Y), protocadherin 12 (PCDH12), protocadherin 17 (PCDH17), protocadherin 18 (PCDH18), protocadherin 19 (PCDH19), protocadherin 20 (PCDH20) cadherin related family member 1 (CDHR1, PCDH21), cadherin related family member 2 (CDHR2, PCDH24), cadherin related family member 3 (CDHR3, CDH28), cadherin related family member 4 (CDHR4, CDH29), cadherin related family member 5 (CDHR5, MU-PCDH), protocadherin related 15 (PCDH15, CDHR15), ret proto-oncogene (RET, CDHR16), cadherin related 23 (CDH23, CDHR23) dachsous cadherin-related 1 (DCHS1, CDHR6), dachsous cadherin-related 2 (DCHS2, CDHR7) FAT atypical cadherin 1 (FAT1, CDHR8), FAT atypical cadherin 2 (FAT2, CDHR9), FAT atypical cadherin 3 (FAT3, CDHR10), FAT atypical cadherin 4 (FAT4, CDHR11) calsyntenin 1 (CLSTN1, CDHR12), calsyntenin 2 (CLSTN2, CDHR13), calsyntenin 3 (CLSTN3, CDHR14)
Official human gene nomenclature (HGNC) symbols are in bold and underlined. Human calcium-dependent membrane proteins with at least two consecutive extracellular cadherin (EC) repeats can be classified into three large families (first column) based on phylogenetic analysis Ref. [1]. The family subtrees in such evolutionary analysis reveal several subfamilies (second column). Members of the subfamilies (third column) have similar functional and structural features as described in the main text.
actions between DCHS1 with 27 EC repeats and FAT4 with 34 EC repeats regulate planar cell polarity and cell proliferation [9]. Classical cadherins are typically found in adherens junctions (AJs). To fit in a 30- to 45-nm intercellular junction, only about double the size of AJs, the giant cadherins were shown to self-bend at certain EC-EC linkers where the typical calcium binding amino acids (AAs) are not conserved [9] (Fig. 1D). Two other cadherin-related proteins PCDH15 (CDHR15) and CDH23 (CDHR23) are found at tip links of stereocilia in the inner ear and are part of the hair-cell transduction machinery [10]. Note that although their official gene symbols refer to protocadherins and classical cadherins, PCDH15 (CDHR15) with 11 EC repeats and CDH23 (CDHR23) with 27 EC repeats are not a protocadherin and not a cadherin, respectively [1]. They form specific heterophilic trans interaction complexes by means of an extended handshake of the EC1EC2 repeats between a PCDH15 cis dimer on the one hand and a CDH23 cis dimer on the other hand (Fig. 1E). Lastly, CDHR2 (PCDH24) and CDHR5 (MU-PCDH) can also heterophilically transinteract to form intermicrovillar adhesion links between adjacent microvilli in the intestinal brush border [11]. Like PCDH15 and CDH23, CDHR2 with nine EC repeats and CDHR5 with four EC repeats have different domain compositions and phylogenetic positions in the superfamily than the protocadherins, but both are often still incorrectly called a protocadherin (PCDH24 and MU-PCDH) rather than a cadherin-related protein.
Protocadherins (PCDH) form in vertebrates the largest cadherin family composed of two subfamilies: clustered and non-clustered protocadherins (Table 1). They play a crucial role in the vertebrate nervous system by generating cell surface diversity and specificity, in that way determining the cellular identity of individual neurons [5]. Mammals have three clusters of protocadherin genes, α-PCDH, βPCDH and γ-PCDH, organized consecutively on the genome. At the cell surface promiscuous cis dimer formation occurs between the membrane-proximal EC repeats (EC6) (Fig. 1B). Two models have been proposed for explaining how such dimeric recognition units can engage in trans interface binding [6]. Tetramers can be formed by head-to-tail EC1 to EC4 trans interactions of the cis dimers. In a second model cis dimers bind two dimeric recognition units on the opposing cell surface and by repeating this a zipper-like assembly can be established (Fig. 1B). The genes of the non-clustered protocadherin subfamily, also called delta-protocadherins (δ-PCDH), are largely dispersed in the genome. Part of the δ-PCDH proteins (the δ2-PCDHs) have six EC repeats like the clustered protocadherins, others (the δ1-PCDHs) possess seven EC repeats. The structure of zebrafish PCDH19, a δ2PCDH, revealed a “forearm handshake” adhesion involving EC1 tot EC4 domains resulting in a fully overlapping antiparallel, homophilic trans dimer (Fig. 1C, [7]). This binding mechanism is similar to the trans interaction mode of clustered protocadherins. Other non-clustered protocadherins are expected to use the same adhesive interface. The cadherin-related family (CDHR) gathers the most diverse members. The calsyntenins, involved in learning and memory formation, have only two EC repeats, which are together able to mediate either homophilic or heterophilic adhesive interactions [8]. It is currently unclear if their primary activity is cell-cell adhesion. Other functions such as secreted ligands or transport chaperones have been suggested. The Dachsous (DCHS1, DCHS2) and FAT (FAT1, −2,−3 and FAT4) cadherins are among the longest cadherins. Heterophilic inter-
1.2. Evolution of the cadherin superfamily The first proteins able to mediate calcium-dependent cell-cell adhesion by means of at least two EC repeats and by this definition belonging to the cadherin superfamily, appeared in the last common ancestor of animals more than 600 million years ago. Only a few
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Fig. 1. Cell-cell adhesion mechanisms in the cadherin superfamily. Each extracellular cadherin (EC) repeat is represented as an ellips being part of cadherin ectodomains in the gap between opposing cell surfaces and numbered starting from the first N-terminal repeat (EC1). Transmembrane regions (TM) are show on top of gray bars. (A) Classical and desmosomal cadherins with 5 EC repeats engage homophilic EC1-EC1 interactions between molecules on opposing cell surfaces (trans), as well as intramolecular interactions between EC1-EC2 repeats of molecules on the same cell surface (cis). (B) Two interaction modes of clustered protocadherins. EC6 repeats are important for cis interactions and domains comprising EC1 to EC4 repeats for trans interactions. (C) Interaction mechanism of non-clustered protocadherins based on the structure of PCDH19. (D) Interaction of the cadherin-related molecules FAT4 and DCHS1 as observed by electron microscopy. (E) Interaction of EC1-EC2 repeats of a PCDH15 (CDHR15) dimer with EC1-EC2 repeats of a CDH23 (CDHR23) dimer. See text for references.
of CELSR, FAT and FAT-like cadherins, suggests that these ancient cadherins emerged as paralogs in the most ancestral animals. Since then, they have been evolving by progressive loss of N-terminal EC repeats in combination with loss of membrane-proximal domains in the ectodomain [12]. The type-III classical cadherin can still be found in e.g. insects, roundworms, fishes and birds, but has been lost in mammals. Instead, the classical cadherin family has greatly expanded in vertebrates with over 30 genes in mammals (Fig. 2). Remarkably, the cytoplasmic domains of these cadherins, which are known to interact with armadillo catenins, have remained highly conserved throughout animal evolution.
representative members of the different cadherin families are found in non-bilaterian, basal animals such as cnidarians e.g. the sea anemone Nematostella and placozoans e.g. Trichoplax [12]. This basic cadherin set is highly conserved, found in nearly all animals and consists of a classical cadherin (CDH family), a nonclassical flamingo/CELSR cadherin (CDH family) and several cadherin-related members such as FAT, FAT-like and DCHS (CDHR family) (Fig. 2). The ancestral classical cadherin (type III) was much longer than the classical cadherins (type I and II) found in vertebrates. The presence of multiple epidermal growth factor like (EGF-like) and laminin G domains in the extracellular region, similar to the domain composition
3
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Fig. 2. Metazoan evolution of cadherin and catenin superfamilies. (Left) Cladogram showing the evolutionary relations among the organisms analyzed: Trichoplax adhaerens for Placozoa; Nematostella vectensis for Cnidaria; Caenorhabditis elegans and Drosophila melanogaster for Ecdysozoa; Aplysia californica for Lophotrochozoa; Ciona intestinalis, Branchiostoma floridae and Strongylocentrotus purpuratus for other deuterostomes; Gallus gallus, Xenopus tropicalis and Danio rerio for other vertebrates; Homo sapiens and Mus musculus for Mammalia. (Right) Number of cadherin family and catenin family members throughout metazoan evolution. Dashed box represents the loss of protocadherins in Ecdysozoans. + indicates duplications of family members in some species in the lineage.
(also called γ-catenin or junction plakoglobin/JUP). The largest subfamily, δ-catenins, has seven members and can be divided into two branches, a CTNND core branch (or p120 branch) and a plakophilin branch. The CTNND core branch has four members: p120 catenin (δ1catenin or CTNND1), ARVCF (armadillo repeat gene deleted in velocardiofacial syndrome), δ-catenin (δ2-catenin or CTNND2) and p0071, also known as plakophilin-4 (PKP4). Finally, the plakophilin branch consists of plakophilin-1 (PKP1), −2 (PKP2) and −3 (PKP3) [15]. While the α-catenin subfamily can be recognized by their vinculin homology domains, the β- and δ-catenin subfamily members possess series of armadillo (Arm) repeats.
Protocadherins were not present in the most ancestral animals. A single protocadherin with seven EC repeats has been identified in cnidarians and several other invertebrates. Ecdysozoa including arthropods and nematodes have lost this protocadherin. Interestingly, a massive expansion of the protocadherin family occurred in vertebrates leading to non-clustered protocadherins with seven or six EC repeats and to numerous clustered protocadherins, each with six EC repeats (Fig. 2). The cadherin-related family is the smallest one with mainly long, atypical cadherins of which FAT has evolved in vertebrates to FAT1, FAT2 and FAT3. Also the exceptionally short calsyntenins expanded to three copies CLSTN1, CLSTN2 and CLSTN3 in vertebrates. Some cadherin-related proteins such as CDHR2 (PCDH24), CDHR5 (MUPCDH), CDHR15 (PCDH15) and CDHR23 (CDH23) appeared only later during animal evolution and their co-evolution was probably due to their mutual heterophilic interactions (see above and Fig. 1E). Other, deviating cadherin-related proteins are mainly found in basal, nonbilaterian animals and appear to be rather lineage-specific. They have been lost in more recently evolved vertebrate and invertebrate animals [12].
2.2. Functions and evolution of β-catenin subfamily members Arm repeats share similar tandem copies of sequence motifs, which are composed of about 42 AAs and form a conserved three-dimensional structure. They were first identified in the Drosophila segment polarity protein Armadillo involved in signal transduction through wingless [16]. Drosophila Armadillo gave the name for this superfamily and is the homolog of mammalian β-catenin. The same motifs were then recognized in the vertebrate homologs of other adherens junctional proteins, such as plakoglobin and p120-catenin [17,18]. The first armadillo structure characterized was the armadillo domain of murine β-catenin, which comprises 12 Arm repeats with each repeat being composed of three helices [19]. Since then the structures and functions of β-catenin have been studied extensively and more than ten crystal structures and 20 interaction partners of β-catenin have meanwhile been reported (reviewed in [20]). Besides its essential role in cell-cell adhesion, β-catenin is one of the key regulators of the canonical Wnt signaling pathway (also referred to as Wnt/β-catenin pathway), an important cascade that regulates cell fate during development. All known extant animals can be divided into five clades: Bilateria, Cnidaria, Placozoa, Ctenophora (comb jellies) and Porifera (sponges). Evolutionary studies on β-catenin by homology searches and phylogenetic analyses revealed that it was present far back in early branching metazoans [15,21] (Fig. 2). A single copy of β-catenin can be found in non-bilaterian animals, such as cnidarian Nematostella vectensis, placozoan Trichoplax adhaerens, ctenophoran Mnemiopsis leidyi and poriferan Amphimedon queenslandica [22]. In line with this, the genomes of these organisms encode also the major components of canonical Wnt signaling, including Frizzled, LRP5/6, Dishevelled and TCF/LEF [23]. While the central armadillo domain of β-catenin, composed of 12 Arm repeats, shows strong sequence conservation throughout metazoan evolution, the terminal domains are more
2. Metazoan evolution and diversity of catenins 2.1. Structures and classification of catenin family members In 1989, Ozawa and colleagues reported an immunoprecipitation experiment where they pulled down uvomorulin (later renamed as Ecadherin) in complex with three proteins of, respectively, 102, 88 and 80 kDa long, and named them as α-, β- and γ-catenin (derived from catena, the Latin word for chain) [13]. Catenins turned out to be key components of the cadherin-based cell adhesion mode. The single-pass transmembrane protein E-cadherin engages in Ca2+-dependent homophilic interactions via their extracellular regions composed of EC domains. At the cytoplasmic side, the tail of E-cadherin forms a complex with armadillo catenins (p120- and β-catenin) and indirectly with α-catenin, which is homologous to vinculin. The latter interaction occurs through β-catenin and connects the E-cadherin cytoplasmic tail with the underlying actin cytoskeleton [14]. This complex is also referred to as the E-cadherin/β-catenin/α-catenin complex or CCC. Based on their sequence homology, the catenin family members can be divided into three subfamilies named after representative members (Fig. 2). The α-catenin subfamily consists of αE-, αN- and αT-catenins, where E stands for epithelial, N for neural, and T for testis, respectively. The β-catenin subfamily comprises β-catenin and plakoglobin 4
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catenin or plakoglobin, it is not clear from which p120 branch member they originated at the origin of vertebrates [21].
divergent and not likely to form a stable folded structure. A recent study, investigating junctional proteins in the non-bilaterian organism N. vectensis, revealed that N. vectensis β-catenin was able to interact with the classical cadherins of N. vectensis, NvCDH1 and NvCDH2, and able to form a ternary CCC [24], indicating the conservation of a cell adhesion function of β-catenin in organisms predating Bilateria. Ancestral β-catenin has gone through several lineage-specific duplications in particular bilaterian lineages. Remarkably, the Caenorhabditis elegans genome encodes four distinct β-catenin orthologs: Hmp-2, Bar-1, Wrm-1 and Sys-1 [25,26]. While a single mammalian β-catenin exerts dual functions in signaling and cell adhesion, in C. elegans the signaling and cell adhesion pools of βcatenin are separate players. For instance, yeast-two hybrid and immunoprecipitation experiments showed that Hmp-2 is the only βcatenin paralog that interacts with the E-cadherin ortholog of C. elegans, Hmr-1 [25]. Further structural and biochemical analysis on the Hmr-1 and Hmp-2 proteins confirmed molecular complex formation between them [27]. This lineage-specific evolution, which resulted in four β-catenin paralogs in C. elegans, provides an opportunity to study the adhesion and signaling roles of β-catenin separately. In vertebrates, β-catenin underwent a duplication event what gave rise to plakoglobin. Similar to β-catenin, plakoglobin has 12 Arm repeats and functions in the adherens junctions. Contrary to β-catenin, plakoglobin is not involved in TCF/LEF-dependent transcriptional activation [28]. However, plakoglobin is essential for the formation of desmosomes as it forms a complex with the desmosomal cadherins desmoglein and desmocollin, plakophilins and desmoplakin [29]. βcatenin is not a structural constituent of desmosomes and does not interact strongly with desmosomal cadherins [30].
3. Non-metazoan origin and diversity of cadherins and catenins
2.3. Functions and evolution of δ-catenin subfamily members
3.1. Cadherin-like molecules in non-metazoans
When compared with the 12 tandem Arm repeats of β-catenin, all seven δ-catenin members have only nine Arm repeats [31,32]. Moreover, the Arm repeats of the δ-catenin members are interrupted by an insert of about 60 AA, situated between the 5th and the 6th Arm repeat. In vertebrates, p120 catenin is a structural component of the CCC, but in addition, it prevents endocytosis of classical cadherins by interacting with their cytoplasmic juxtamembrane domains at a site, which overlaps with the endocytic dileucine motif. By masking this motif, vertebrate p120 catenin prevents the interaction between the cytoplasmic tail of classical cadherins on the one hand and Presenilin-1 and Hakai on the other hand (reviewed in [33]). Similar to p120 catenin, the other CTNND core branch members, Ctnnd2, Arcvf and p0071, are involved in the regulation of cadherin stability at cell–cell junctions (reviewed in [34]). Moreover, all four members of this branch participate in actin cytoskeleton remodeling by regulating Rho family GTPases (reviewed in [35]). Except for the sea squirt Ciona intestinalis and sea anemone Nematostella vectensis, where two copies of δ-catenin members are found, all invertebrate animals have a single ancestral δ-catenin (Fig. 2). Our previous comparative sequence analyses on δ-catenin subfamily members revealed that the first duplication event has occurred at the origin of vertebrates. In line with this, the two copies of δ-catenins from the tunicate C. intestinalis, CiCtnnd-A and CiCtnndB, form separate clades with vertebrate Ctnnd1/Arvcf and Ctnnd2/ Pkp4 proteins [22]. Plakophilins were identified as desmosomal plaque proteins that are essential for the stabilization and the formation of desmosomes via their association with desmosomal cadherins (reviewed in [36]). Plakophilin encoding genes are located on different chromosomes but these genes show exon/intron boundaries that are at almost identical positions of the respectively encoded AA sequences. This suggests that they originated from a common ancestor quite recently in evolution. Although plakophilins show higher similarity to the p120 branch members than to β-
Some form of cell-cell adhesion was required to evolve from unicellularity to the first multicellular animals (Metazoa). For cadherins to play a role in this, cadherin-like molecules had to be present before the appearance of the first animals. It was nonetheless some surprise that researchers found cadherin-like genes in choanoflagellates, the closest single-celled relatives of animals [41]. Meanwhile, cadherin-like genes have been reported in several other non-metazoan species [42–45]. However, currently there is neither functional nor structural evidence that these cadherin-like molecules act as calciumdependent cell adhesion molecules as extensively documented in animal cell-cell adhesion. Indeed, these non-metazoan molecules needed to be classified in a separate cadherin-like (CDHL) family (not to be confused with the cadherin-related or CDHR family). For instance, the cadherin-like domains found in Proteobacteria and Cyanobacteria do not have the typical conserved calcium-binding motifs LDRE and DxNDN found in the whole cadherin superfamily [43]. Structure determination of the predicted cadherin-like domain in α-dystroglycans [42] revealed an Ig-like domain different from the typical cadherin fold [46]. In conclusion, to determine if some of these cadherin-like (CDHL) proteins truly belong to the cadherin superfamily, additional phylogenetic and structural analyses are required to elucidate whether they share any functional or structural characteristics with members of the three established cadherin families, cadherins, protocadherins and cadherin-related proteins.
2.4. Functions and evolution of α-catenin subfamily members α-Catenin subfamily members function as a bridge between the actin bundles and the E-cadherin/p120 catenin/β-catenin heterotrimer. While the N-terminal domain of α-catenin binds this of βcatenin, the C-terminal part interacts at the same time with the actin filaments [37]. In addition, α-catenin homodimers can also bind actin filaments and regulate the actin cytoskeleton by suppressing Arp2/3mediated actin polymerization [38,39]. Both CCC-bound monomeric αcatenin and α-catenin homodimers are required for stable cell-cell adhesion [40]. In particular αE-catenin has been studied extensively and this is also the most widely expressed family member. αT-catenin expression is largely restricted to cardiomyocytes and αN-catenin is a major constituent of intercellular junctions in the neural system. αN- and αE-catenins show more than 80% sequence identity, whereas αTcatenin is more distantly related to these two α-catenins. Similar to the evolutionary history of the two armadillo catenin subfamilies, a single α-catenin ortholog can be found in early diverging metazoan species (Fig. 2). Previous phylogenetic analyses identified αN-catenin as the ancestor of all α-catenins. In vertebrates, αN-catenin gave rise to αEcatenin, while the most recently evolved member, αT-catenin, arose as a result of an amniote-specific gene duplication event [15,21].
3.2. Catenin-like molecules in non-metazoans Sequence searches for β-catenin proteins revealed that no β-catenin homolog can be found in choanoflagellates Monosiga brevicollis and Salpingoeca rosetta, which are the closest known relatives of metazoans [21]. However, in other non-metazoan species β-catenin like proteins have been reported, such as unicellular yeast Saccharomyces cerevisiae Vac8p and slime mold Dictyostelium discoideum Aardvark which share 22% and 18% identity to mammalian β5
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catenin, respectively. Although D. discoideum lacks an ortholog of a classical cadherin, its β-catenin ortholog Aardvark is able to interact with an α-catenin-like gene product, which is essential for the formation of a particular polarized epithelium [47]. Although the catenin family members share the same core name ‘catenin’, the three subfamilies, α-, β- and δ-, have different evolutionary origins. Our recent study on the evolution of the Arm repeat superfamily revealed that β- and δ-catenins are not evolutionarily related to each other and have evolved from different premetazoan ancestors [22]. Bayesian phylogeny suggests that while the δ-catenins and armadillo formins share a common ancestral origin, β-catenin and the related plakoglobin are related to an uncharacterized protein called Armadillo repeat-containing protein 6 (Armc6) [22]. Although biochemical analyses suggest that the α-catenin protein from Dictyostelium discoideum functions like metazoan α-catenin [47], phylogenetic analysis on the vinculin gene family positions this D. discoideum α-catenin rather as an ortholog of vinculin [48]. More research on non-metazoan organisms, such as Choanoflagellida and Capsaspora, is required to explore the function and evolutionary origin of metazoan and non-metazoan α-catenin gene family members. Acknowledgements We thank our colleagues for helpful discussions. This work was supported by the Research Foundation – Flanders (FWO-Vlaanderen, Award G.0320.11N), the Belgian Science Policy (Interuniversity Attraction Poles – Award IAP7/07), and the Special Research Fund of Ghent University (Award BOF 01J14211). References [1] P. Hulpiau, F. van Roy, Molecular evolution of the cadherin superfamily, Int J. Biochem. Cell Biol. 41 (2) (2009) 349–369 (doi:S1357-2725)(08)(00404-4 )(pii) (10.1016/j.biocel.2008.09.027). [2] O.J. Harrison, X. Jin, S. Hong, F. Bahna, G. Ahlsen, J. Brasch, Y. Wu, J. Vendome, K. Felsovalyi, C.M. Hampton, R.B. Troyanovsky, A. Ben-Shaul, J. Frank, S.M. Troyanovsky, L. Shapiro, B. Honig, The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins, Structure 19 (2) (2011) 244–256 (doi:S0969-2126)(11)(00003-7 )(pii)(10.1016/j.str.2010.11.016). [3] S.D. Patel, C. Ciatto, C.P. Chen, F. Bahna, M. Rajebhosale, N. Arkus, I. Schieren, T.M. Jessell, B. Honig, S.R. Price, L. Shapiro, Type II cadherin ectodomain structures: implications for classical cadherin specificity, Cell 124 (6) (2006) 1255–1268. [4] W. Baumgartner, M.W. Wendeler, A. Weth, R. Koob, D. Drenckhahn, R. Gessner, Heterotypic trans-interaction of LI- and E-cadherin and their localization in plasmalemmal microdomains, J. Mol. Biol. 378 (1) (2008) 44–54. [5] T. Yagi, Genetic basis of neuronal individuality in the mammalian brain, J. Neurogenet. 27 (3) (2013) 97–105. http://dx.doi.org/10.3109/ 01677063.2013.801969. [6] K.M. Goodman, R. Rubinstein, C.A. Thu, S. Mannepalli, F. Bahna, G. Ahlsen, C. Rittenhouse, T. Maniatis, B. Honig, L. Shapiro, Gamma-protocadherin structural diversity and functional implications, Elife (2016) 5. http://dx.doi.org/10.7554/ eLife.20930. [7] S.R. Cooper, J.D. Jontes, M. Sotomayor, Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy, Elife (2016) 5. http:// dx.doi.org/10.7554/eLife.18529. [8] H. Ortiz-Medina, M.R. Emond, J.D. Jontes, Zebrafish calsyntenins mediate homophilic adhesion through their amino-terminal cadherin repeats, Neuroscience 286 (2015) 87–96. http://dx.doi.org/10.1016/j.neuroscience.2014.11.030. [9] Y. Tsukasaki, N. Miyazaki, A. Matsumoto, S. Nagae, S. Yonemura, T. Tanoue, K. Iwasaki, M. Takeichi, Giant cadherins fat and dachsous self-bend to organize properly spaced intercellular junctions, Proc. Natl. Acad. Sci. USA 111 (45) (2014) 16011–16016. http://dx.doi.org/10.1073/pnas.1418990111. [10] R. Araya-Secchi, B.L. Neel, M. Sotomayor, An elastic element in the protocadherin15 tip link of the inner ear, Nat. Commun. 7 (2016) 13458. http://dx.doi.org/ 10.1038/ncomms13458. [11] S.W. Crawley, M.S. Mooseker, M.J. Tyska, Shaping the intestinal brush border, J. Cell Biol. 207 (4) (2014) 441–451. http://dx.doi.org/10.1083/jcb.201407015. [12] P. Hulpiau, F. Van Roy, New insights into the evolution of metazoan cadherins, Mol. Biol. Evol. 28 (1) (2011) 647–657 (doi:msq233 )(pii)(10.1093/molbev/ msq233). [13] M. Ozawa, H. Baribault, R. Kemler, The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species, EMBO J. 8 (6) (1989) 1711–1717. [14] M. Takeichi, Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling, Nat. Rev. Mol. Cell Biol. 15 (6) (2014) 397–410. http://dx.doi.org/
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