SMART MODE:

NORMAL GENOMIC

• Kister AE, Roytberg MA, Chothia C, Vasiliev JM, Gelfand IM
• The sequence determinants of cadherin molecules.
• Protein Sci. 2001; 10: 1801-10
• Display abstract

• The sequence and structural analysis of cadherins allow us to find sequence determinants-a few positions in sequences whose residues are characteristic and specific for the structures of a given family. Comparison of the five extracellular domains of classic cadherins showed that they share the same sequence determinants despite only a nonsignificant sequence similarity between the N-terminal domain and other extracellular domains. This allowed us to predict secondary structures and propose three-dimensional structures for these domains that have not been structurally analyzed previously. A new method of assigning a sequence to its proper protein family is suggested: analysis of sequence determinants. The main advantage of this method is that it is not necessary to know all or almost all residues in a sequence as required for other traditional classification tools such as BLAST, FASTA, and HMM. Using the key positions only, that is, residues that serve as the sequence determinants, we found that all members of the classic cadherin family were unequivocally selected from among 80,000 examined proteins. In addition, we proposed a model for the secondary structure of the cytoplasmic domain of cadherins based on the principal relations between sequences and secondary structure multialignments. The patterns of the secondary structure of this domain can serve as the distinguishing characteristics of cadherins.

• McCarthy M, Na E, Neyt C, Langston A, Fishell G
• Calcium-dependent adhesion is necessary for the maintenance of prosomeres.
• Dev Biol. 2001; 233: 80-94
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• Cell adhesion has been suggested to function in the establishment and maintenance of the segmental organization of the central nervous system. Here we tested the role of different classes of adhesion molecules in prosencephalic segmentation. Specifically, we examined the ability of progenitors from different prosomeres to reintegrate and differentiate within various brain regions after selective maintenance or removal of different classes of calcium-dependent versus -independent surface molecules. This analysis implicates calcium-dependent adhesion molecules as central to the maintenance of prosomeres. Only conditions that spared calcium-dependent adhesion systems but ablated more general (calcium-independent) adhesion systems resulted in prosomere-specific integration after transplantation. Among the members of this class of adhesion molecules, R-cadherin shows a striking pattern of prosomeric expression during development. To test whether expression of this molecule was sufficient to direct progenitor integration to prosomeres expressing R-cadherin, we used a retroviral-mediated gain-of-function approach. We found that progenitors originally isolated from prosomere P2 (a region which does not express R-cadherin), when forced to express this molecule, can now integrate more readily into R-cadherin-expressing regions, such as the cortex, the ventral thalamus, and the hypothalamus. Nonetheless, our analysis suggests that while calcium-dependent molecules are able to direct prosomere-specific integration, they are not sufficient to induce progenitors to change their regional identity. While diencephalic progenitors from R-cadherin-expressing regions of prosomere 5 could integrate into R-cadherin-expressing regions of the cortex, they did not express the cortex-specific gene Emx1 or the telencephalic-specific gene Bf-1. Furthermore, diencephalic progenitors that integrate heterotopically into the cortex do not persist postnatally, whereas the same progenitors survive and differentiate when they integrate homotopically into the diencephalon. Together our results implicate calcium-dependent adhesion molecules as key mediators of prosomeric organization but suggest that they are not sufficient to bestow regional identities. Copyright 2001 Academic Press.

• Sivasankar S, Gumbiner B, Leckband D
• Direct measurements of multiple adhesive alignments and unbinding trajectories between cadherin extracellular domains.
• Biophys J. 2001; 80: 1758-68
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• Direct measurements of the interactions between antiparallel, oriented monolayers of the complete extracellular region of C-cadherin demonstrate that, rather than binding in a single unique orientation, the cadherins adhere in three distinct alignments. The strongest adhesion is observed when the opposing extracellular fragments are completely interdigitated. A second adhesive alignment forms when the interdigitated proteins separate by 70 +/- 10 A. A third complex forms at a bilayer separation commensurate with the approximate overlap of cadherin extracellular domains 1 and 2 (CEC1-2). The locations of the energy minima are independent of both the surface density of bound cadherin and the stiffness of the force transducer. Using surface element integration, we show that two flat surfaces that interact through an oscillatory potential will exhibit discrete minima at the same locations in the force profile measured between hemicylinders covered with identical materials. The measured interaction profiles, therefore, reflect the relative separations at which the antiparallel proteins adhere, and are unaffected by the curvature of the underlying substrate. The successive formation and rupture of multiple protein contacts during detachment can explain the observed sluggish unbinding of cadherin monolayers. Velocity-distance profiles, obtained by quantitative video analysis of the unbinding trajectory, exhibit three velocity regimes, the transitions between which coincide with the positions of the adhesive minima. These findings suggest that cadherins undergo multiple stage unbinding, which may function to impede adhesive failure under force.

• Noren NK, Niessen CM, Gumbiner BM, Burridge K
• Cadherin engagement regulates Rho family GTPases.
• J Biol Chem. 2001; 276: 33305-8
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• The formation of cell-cell adherens junctions is a cadherin-mediated process associated with reorganization of the actin cytoskeleton. Because Rho family GTPases regulate actin dynamics, we investigated whether cadherin-mediated adhesion regulates the activity of RhoA, Rac1, and Cdc42. Confluent epithelial cells were found to have elevated Rac1 and Cdc42 activity but decreased RhoA activity when compared with low density cultures. Using a calcium switch method to manipulate junction assembly, we found that induction of cell-cell junctions increased Rac1 activity, and this was inhibited by E-cadherin function-blocking antibodies. Using the same calcium switch procedure, we found little effect on RhoA activity during the first hour of junction assembly. However, over several hours, RhoA activity significantly decreased. To determine whether these effects are mediated directly through cadherins or indirectly through engagement of other surface proteins downstream from junction assembly, we used a model system in which cadherin engagement is induced without cell-cell contact. For these experiments, Chinese hamster ovary cells expressing C-cadherin were plated on the extracellular domain of C-cadherin immobilized on tissue culture plates. Whereas direct cadherin engagement did not stimulate Cdc42 activity, it strongly inhibited RhoA activity but increased Rac1 activity. Deletion of the C-cadherin cytoplasmic domain abolished these effects.

• Chappuis-Flament S, Wong E, Hicks LD, Kay CM, Gumbiner BM
• Multiple cadherin extracellular repeats mediate homophilic binding and adhesion.
• J Cell Biol. 2001; 154: 231-43
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• The extracellular homophilic-binding domain of the cadherins consists of 5 cadherin repeats (EC1-EC5). Studies on cadherin specificity have implicated the NH(2)-terminal EC1 domain in the homophilic binding interaction, but the roles of the other extracellular cadherin (EC) domains have not been evaluated. We have undertaken a systematic analysis of the binding properties of the entire cadherin extracellular domain and the contributions of the other EC domains to homophilic binding. Lateral (cis) dimerization of the extracellular domain is thought to be required for adhesive function. Sedimentation analysis of the soluble extracellular segment of C-cadherin revealed that it exists in a monomer-dimer equilibrium with an affinity constant of approximately 64 microm. No higher order oligomers were detected, indicating that homophilic binding between cis-dimers is of significantly lower affinity. The homophilic binding properties of a series of deletion constructs, lacking successive or individual EC domains fused at the COOH terminus to an Fc domain, were analyzed using a bead aggregation assay and a cell attachment-based adhesion assay. A protein with only the first two NH(2)-terminal EC domains (CEC1-2Fc) exhibited very low activity compared with the entire extracellular domain (CEC1-5Fc), demonstrating that EC1 alone is not sufficient for effective homophilic binding. CEC1-3Fc exhibited high activity, but not as much as CEC1-4Fc or CEC1-5Fc. EC3 is not required for homophilic binding, however, since CEC1-2-4Fc and CEC1-2-4-5Fc exhibited high activity in both assays. These and experiments using additional EC combinations show that many, if not all, the EC domains contribute to the formation of the cadherin homophilic bond, and specific one-to-one interaction between particular EC domains may not be required. These conclusions are consistent with a previous study on direct molecular force measurements between cadherin ectodomains demonstrating multiple adhesive interactions (Sivasankar, S., W. Brieher, N. Lavrik, B. Gumbiner, and D. Leckband. 1999. PROC: Natl. Acad. Sci. USA. 96:11820-11824; Sivasankar, S., B. Gumbiner, and D. Leckband. 2001. Biophys J. 80:1758-68). We propose new models for how the cadherin extracellular repeats may contribute to adhesive specificity and function.

• Angst BD, Marcozzi C, Magee AI
• The cadherin superfamily: diversity in form and function.
• J Cell Sci. 2001; 114: 629-41
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• Over recent years cadherins have emerged as a growing superfamily of molecules, and a complex picture of their structure and their biological functions is becoming apparent. Variation in their extracellular region leads to the large potential for recognition properties of this superfamily. This is demonstrated strikingly by the recently discovered FYN-binding CNR-protocadherins; these exhibit alternative expression of the extracellular portion, which could lead to distinct cell recognition in different neuronal populations, whereas their cytoplasmic part, and therefore intracellular interactions, is constant. Diversity in the cytoplasmic moiety of the cadherins imparts specificity to their interactions with cytoplasmic components; for example, classical cadherins interact with catenins and the actin filament network, desmosomal cadherins interact with catenins and the intermediate filament system and CNR-cadherins interact with the SRC-family kinase FYN. Recent evidence suggests that CNR-cadherins, 7TM-cadherins and T-cadherin, which is tethered to the membrane by a GPI anchor, all localise to lipid rafts, specialised cell membrane domains rich in signalling molecules. Originally thought of as cell adhesion molecules, cadherin superfamily molecules are now known to be involved in many biological processes, such as cell recognition, cell signalling, cell communication, morphogenesis, angiogenesis and possibly even neurotransmission.

• Knudsen KA, Soler AP
• Cadherin-mediated cell-cell interactions.
• Methods Mol Biol. 2000; 137: 409-40

• Alattia JR, Tong FK, Tong KI, Ikura M
• Sequence-specific resonance assignments and partial unfolding of extracellular domains II and III of E-cadherin.
• J Biomol NMR. 2000; 16: 181-2

• Thoreson MA et al.
• Selective uncoupling of p120(ctn) from E-cadherin disrupts strong adhesion.
• J Cell Biol. 2000; 148: 189-202
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• p120(ctn) is a catenin whose direct binding to the juxtamembrane domain of classical cadherins suggests a role in regulating cell-cell adhesion. The juxtamembrane domain has been implicated in a variety of roles including cadherin clustering, cell motility, and neuronal outgrowth, raising the possibility that p120 mediates these activities. We have generated minimal mutations in this region that uncouple the E-cadherin-p120 interaction, but do not affect interactions with other catenins. By stable transfection into E-cadherin-deficient cell lines, we show that cadherins are both necessary and sufficient for recruitment of p120 to junctions. Detergent-free subcellular fractionation studies indicated that, in contrast to previous reports, the stoichiometry of the interaction is extremely high. Unlike alpha- and beta-catenins, p120 was metabolically stable in cadherin-deficient cells, and was present at high levels in the cytoplasm. Analysis of cells expressing E-cadherin mutant constructs indicated that p120 is required for the E-cadherin-mediated transition from weak to strong adhesion. In aggregation assays, cells expressing p120-uncoupled E-cadherin formed only weak cell aggregates, which immediately dispersed into single cells upon pipetting. As an apparent consequence, the actin cytoskeleton failed to insert properly into peripheral E-cadherin plaques, resulting in the inability to form a continuous circumferential ring around cell colonies. Our data suggest that p120 directly or indirectly regulates the E-cadherin-mediated transition to tight cell-cell adhesion, possibly blocking subsequent events necessary for reorganization of the actin cytoskeleton and compaction.

• Kasper C et al.
• Structural basis of cell-cell adhesion by NCAM.
• Nat Struct Biol. 2000; 7: 389-93
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• The neural cell adhesion molecule NCAM, a member of the immunoglobulin superfamily, mediates cell-cell recognition and adhesion via a homophilic interaction. NCAM plays a key role during development and regeneration of the nervous system and is involved in synaptic plasticity associated with memory and learning. The 1.85 A crystal structure of the two N-terminal extracellular domains of NCAM reported here provides a structural basis for the homophilic interaction. The molecular packing of the two-domain structure reveals a cross shaped antiparallel dimer, and provides fundamental insight into trans-cellular recognition mediated by NCAM.

• Taraszka KS, Higgins JM, Tan K, Mandelbrot DA, Wang JH, Brenner MB
• Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin.
• J Exp Med. 2000; 191: 1555-67
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• Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best characterized example of lymphocyte adhesion to a tissue-specific cell adhesion molecule, as opposed to a vascular endothelial adhesion molecule, is the interaction between integrin alpha(E)beta(7) on intraepithelial lymphocytes and E-cadherin on epithelial cells. However, the molecular basis for an integrin-cadherin interaction is not well defined. Realization that the cadherin domain adopts a topology similar to the immunoglobulin (Ig) fold suggested that integrin recognition of E-cadherin might be similar to recognition of Ig superfamily ligands. Thus, we modeled domain 1 of human E-cadherin and studied the role of solvent-exposed loops that connect Ig-like core-forming beta strands. Mutational analyses localized the integrin alpha(E)beta(7) recognition site to the top of domain 1 at the face formed by the BC and FG loops, a site distinct from the region recognized in intercellular adhesion molecule (ICAM)-1, -2, and -3, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), vascular cell adhesion molecule 1 (VCAM-1), and fibronectin by their integrin ligands. Moreover, the integrin alpha(E)beta(7) binding site is distinct from the homophilic binding site on E-cadherin. These studies provide a conceptual basis for integrin-cadherin binding and extend the model that an Ig-like fold can serve as a scaffold for recognition.

• Gumbiner BM
• Regulation of cadherin adhesive activity.
• J Cell Biol. 2000; 148: 399-404

• Murase S et al.
• Lateral clustering of cadherin-4 without homophilic interaction: possible involvement in the concentration process at cell-cell adhesion sites as well as in the cell adhesion activity.
• Biochem Biophys Res Commun. 2000; 276: 1191-8
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• It is thought that the concentration of classic cadherins at cell-cell adhesion sites is essential for generating strong cell-cell adhesion activity, but the mechanism is not well understood. To clarify the structural basis of the concentration process and the cell adhesion activity, we constructed various mutants of cadherin-4 and examined the adhesion properties of the transfectants. A deletion mutant lacking the entire cytoplasmic domain had weak, but significant Ca(2+)-dependent cell adhesion activity. Interestingly, the deletion mutant showed intrinsic cluster formation in the absence of cell-cell adhesion, possible lateral cluster formation. The cytoplasmic domain-deleted cadherin-4 containing the mutation of Trp-2 to Ala, which is known to inhibit the strand dimer formation required for the cell-cell adhesion, retained the possible activity of lateral cluster formation, supporting this notion. These results suggest that the extracellular domain has intrinsic activity of lateral cluster formation. Indeed, deletion of a cadherin repeat in the extracellular domain significantly reduced or abolished the lateral cluster formation as well as the concentration of cadherin-4 at cell-cell contact sites and cell adhesion activity. When transfectants of the cytoplasmic domain-deleted cadherin-4 made cell-cell contact and formed intimate cell-cell adhesion, the lateral clusters of cadherin-4 initially gathered at cell-cell contact sites, and a smooth linear concentration was gradually formed along the cell-cell adhesion interface. The results suggest that the lateral cluster formation is involved in the concentration process of cadherin-4 at cell-cell adhesion sites, hence in the strong cell adhesion activity of cadherin-4 as well.

• Leckband D, Sivasankar S
• Mechanism of homophilic cadherin adhesion.
• Curr Opin Cell Biol. 2000; 12: 587-92
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• Direct measurements of the distance-dependent forces between membrane-bound cadherins were used to test current models of homophilic cadherin interactions. The results reveal a complex binding mechanism in which the proteins adhere in multiple alignments that involve more than the amino-terminal domains.

• Bruses JL
• Cadherin-mediated adhesion at the interneuronal synapse.
• Curr Opin Cell Biol. 2000; 12: 593-7
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• One of the recent advances in the molecular definition of a synapse has been the identification of cadherins as major structural components. The presence of classic (N- and E-) cadherins in the synaptic complex is not surprising considering the ultrastructural similarities between interneuronal synapses and the adhesive junctions formed between epithelial cells. However, the role of these adhesion molecules and their junctions in this context is likely to encompass both developmental and physiological phenomena that are unique to the synapse. Moreover, the recent finding that a much broader family of cadherin-related receptors is also located at the synaptic complex has fuelled speculation that cadherins have a role in generation of specificity in synaptic connectivity as well as structure.

• Wu Q, Maniatis T
• A striking organization of a large family of human neural cadherin-like cell adhesion genes.
• Cell. 1999; 97: 779-90
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• We have identified 52 novel human cadherin-like genes organized into three closely linked clusters. Comparison of the genomic DNA sequences with those of representative cDNAs reveals a striking genomic organization similar to that of immunoglobulin and T cell receptor gene clusters. The N-terminal extracellular and transmembrane domains of each cadherin protein are encoded by a distinct and unusually large exon. These exons are organized in a tandem array. By contrast, the C-terminal cytoplasmic domain of each protein is identical and is encoded by three small exons located downstream from the cluster of N-terminal exons. This unusual organization has interesting implications regarding the molecular code required to establish complex networks of neuronal connections in the brain and the mechanisms of cell-specific cadherin-like gene expression.

• Braga VM
• Small GTPases and regulation of cadherin dependent cell-cell adhesion.
• Mol Pathol. 1999; 52: 197-202
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• Cadherins belong to a superfamily of cell-cell adhesion receptors that bind to the same type of molecules (homotypic interaction) in a calcium dependent manner. Different members of the family are found in a wide variety of cell types and cadherin adhesive function plays a role in cell fate, segregation, and differentiation, which ensures the higher order of organisation found in many tissues. This review will focus on the role that cadherin adhesiveness plays in the differentiation of epithelial cells, and how cadherin function can be regulated by proteins of the small GTPase family. In the text, readers are referred to recent reviews and other chapters covering important topics that are not discussed here because of space limitation.

• Obst-Pernberg K, Redies C
• Cadherins and synaptic specificity.
• J Neurosci Res. 1999; 58: 130-8
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• Cadherins are a family of cell-cell adhesion molecules that regulate morphogenesis in a variety of organs during development. In this review, we summarize recent evidence that cadherins may be involved in synaptogenesis in the vertebrate central nervous system. The first cadherin identified in synapses was N-cadherin, which is a major glycoprotein in postsynaptic density preparations. Electron microscopic studies have shown that this molecule is present at the synaptic cleft, bordering the transmitter release zone. To date, several other cadherins have also been found in synaptic junctions. Some cadherins have been observed in distinct subsets of synapses. The homophilic binding properties of cadherins may provide a molecular basis for the adhesive interactions between opposing synaptic membranes, and cadherins may promote a stable locking-in of pre- and postsynaptic membranes. Thus, cadherins may play a role in the formation and maintenance of synapses. Cadherin expression in synapses has been studied during development, regeneration, and activity-dependent plasticity. Moreover, it has been shown that each cadherin is expressed in specific neural circuits. In this context, we discuss the possibility that the differential expression of cadherins in the nervous system provides an adhesive framework for synaptic specificity.

• Alattia JR, Kurokawa H, Ikura M
• Structural view of cadherin-mediated cell-cell adhesion.
• Cell Mol Life Sci. 1999; 55: 359-67
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• Following the multiplication of biochemical, biophysical and structural studies describing cadherin molecules and their interactions, several ideas have emerged to explain the mechanisms of cadherin-mediated cell adhesion. Although different models were proposed for cadherin interactions, a consensus has come forth considering lateral dimerization of cadherins as being a central component of the cell-cell adhesion process. This review summarizes the recent development in structural studies of cadherin.

• Zhong Y, Brieher WM, Gumbiner BM
• Analysis of C-cadherin regulation during tissue morphogenesis with an activating antibody.
• J Cell Biol. 1999; 144: 351-9
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• The regulation of cadherin-mediated adhesion at the cell surface underlies several morphogenetic processes. To investigate the role of cadherin regulation in morphogenesis and to begin to analyze the molecular mechanisms of cadherin regulation, we have screened for monoclonal antibodies (mAbs) that allow us to manipulate the adhesive state of the cadherin molecule. Xenopus C-cadherin is regulated during convergent extension movements of gastrulation. Treatment of animal pole tissue explants (animal caps) with the mesoderm-inducing factor activin induces tissue elongation and decreases the strength of C-cadherin-mediated adhesion between blastomeres (Brieher, W.M., and B.M. Gumbiner. 1994. J. Cell Biol. 126:519-527). We have generated a mAb to C-cadherin, AA5, that restores strong adhesion to activin-treated blastomeres. This C-cadherin activating antibody strongly inhibits the elongation of animal caps in response to activin without affecting mesodermal gene expression. Thus, the activin-induced decrease in C-cadherin adhesive activity appears to be required for animal cap elongation. Regulation of C-cadherin and its activation by mAb AA5 involve changes in the state of C-cadherin that encompass more than changes in its homophilic binding site. Although mAb AA5 elicited a small enhancement in the functional activity of the soluble C-cadherin ectodomain (CEC1-5), it was not able to restore cell adhesion activity to mutant C-cadherin lacking its cytoplasmic tail. Furthermore, activin treatment regulates the adhesion of Xenopus blastomeres to surfaces coated with two other anti-C-cadherin mAbs, even though these antibodies probably do not mediate adhesion through a normal homophilic binding mechanism. Moreover, mAb AA5 restores strong adhesion to these antibodies. mAb AA5 only activates adhesion of blastomeres to immobilized CEC1-5 when it binds to C-cadherin on the cell surface. It does not work when added to CEC1-5 on the substrate. Together these findings suggest that the regulation of C-cadherin by activin and its activation by mAb AA5 involve changes in its cellular organization or interactions with other cell components that are not intrinsic to the isolated protein.

• Steinberg MS, McNutt PM
• Cadherins and their connections: adhesion junctions have broader functions.
• Curr Opin Cell Biol. 1999; 11: 554-60
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• Cadherins - a family of cell-cell adhesion molecules - are linked to the actin cytoskeleton via intervening proteins. Recent results address molecular explanations for observed cadherin behavior, point to signals that regulate adhesion by modulating elements of the cadherin-associated complex, challenge the belief that different cadherins generally cannot cross-adhere, and highlight instructive roles for cadherins in cell signaling and differentiation.

• Troyanovsky SM
• Mechanism of cell-cell adhesion complex assembly.
• Curr Opin Cell Biol. 1999; 11: 561-6
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• Cell-cell adhesion complexes play an important role in the organization and behavior of cells in tissues. An important step in the formation of such complexes is the clustering of the adhesion receptors; this is critical for proper adhesion, for anchorage of the cytoskeleton to the plasma membrane, and for generation of different intracellular signals. Recent advances reveal that several interconnected mechanisms are responsible for clustering of the different adhesion receptors.

• Kusumi A, Suzuki K, Koyasako K
• Mobility and cytoskeletal interactions of cell adhesion receptors.
• Curr Opin Cell Biol. 1999; 11: 582-90
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• Clustering of cell adhesion receptors and their interactions with the cytoskeleton are key events in the formation and function of cell adhesion structures. On the free cell surface, cadherin molecules interact with the cytoskeleton/membrane skeleton by being bound or corralled, and such interactions are greatly enhanced by the formation of cadherin oligomers. Corralled cadherin molecules undergo hop diffusion from one compartment to an adjacent one (membrane skeleton fence model), which prompts the initial formation of small adhesion clusters at cell-cell contact sites, but larger-scale assemblies of cadherin and actin filaments might require a further co-ordinated recruitment of these molecules.

• Kurokawa H, Alattia JR, Ikura M
• [Structural biology of cell adhesion molecule cadherins]
• Tanpakushitsu Kakusan Koso. 1999; 44: 311-7

• Provost E, Rimm DL
• Controversies at the cytoplasmic face of the cadherin-based adhesion complex.
• Curr Opin Cell Biol. 1999; 11: 567-72
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• Cadherin-mediated cell-cell interactions are modulated by protein interactions at the cytoplasmic face of the membrane. Recent work has shown that phosphorylation of both p120(ctn) and beta-catenin affects their interaction with cadherins and the molecular connections to the cytoskeleton. The cytoskeletal connections most probably include interactions between alpha-catenin, and/or alpha-actinin, vinculin, ZO-1, actin and possibly spectrin.

• Shan WS, Koch A, Murray J, Colman DR, Shapiro L
• The adhesive binding site of cadherins revisited.
• Biophys Chem. 1999; 82: 157-63
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• Cadherins are single-pass transmembrane proteins that, through their homophilic specificity, function in selective cell adhesion and sorting. They have a modular structure that includes an ectodomain composed of tandem 'cadherin domains,' which have a beta-sandwich topology similar to that of immunoglobulin domains. Some early experiments suggest that, for the 'classical' cadherins, the adhesive specificity is encoded in the membrane-distal amino-terminal cadherin domain. Here, we review these data, and present new data that supports this idea.

• Clarke J, Cota E, Fowler SB, Hamill SJ
• Folding studies of immunoglobulin-like beta-sandwich proteins suggest that they share a common folding pathway.
• Structure Fold Des. 1999; 7: 1145-53
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• BACKGROUND: Are folding pathways conserved in protein families? To test this explicitly and ask to what extent structure specifies folding pathways requires comparison of proteins with a common fold. Our strategy is to choose members of a highly diverse protein family with no conservation of function and little or no sequence identity, but with structures that are essentially the same. The immunoglobulin-like fold is one of the most common structural families, and is subdivided into superfamilies with no detectable evolutionary or functional relationship. RESULTS: We compared the folding of a number of immunoglobulin-like proteins that have a common structural core and found a strong correlation between folding rate and stability. The results suggest that the folding pathways of these immunoglobulin-like proteins share common features. CONCLUSIONS: This study is the first to compare the folding of structurally related proteins that are members of different superfamilies. The most likely explanation for the results is that interactions that are important in defining the structure of immunoglobulin-like proteins are also used to guide folding.

• Vleminckx K, Kemler R
• Cadherins and tissue formation: integrating adhesion and signaling.
• Bioessays. 1999; 21: 211-20
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• Cadherins and other cell-substrate and cell-cell adhesion molecules play an essential role during development. Through their cytoplasmic interaction with the cytoskeleton, cell adhesion molecules physically link cells with the extracellular matrix and/or with each other. These interactions create architectural and structural entities that enable the tissues in the embryo to restrain the physical forces encountered during development. Regulated cell adhesion is also often the driving force of morphogenetic movements. This review goes beyond the adhesive aspect of cadherins, focusing on their roles as signaling molecules in development. We discuss how cadherins, through their effects on cell proliferation, cell death, cell polarization, and differentiation, play a role in the formation of tissues and organs in the developing embryo.

• Koch AW, Bozic D, Pertz O, Engel J
• Homophilic adhesion by cadherins.
• Curr Opin Struct Biol. 1999; 9: 275-81
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• Cadherins mediate cell-cell adhesion through homophilic interactions. High-resolution structures have greatly enhanced our understanding of this phenomenon over the past few years. Nonetheless, some of the original concepts about cadherin interactions need revision, with the new structural and additional mutagenesis data currently available. Furthermore, in vivo studies on cadherins have provided supplementary information.

• Adams CL, Nelson WJ
• Cytomechanics of cadherin-mediated cell-cell adhesion.
• Curr Opin Cell Biol. 1998; 10: 572-7
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• Cadherin-mediated adhesion regulates transitions from initial cell-cell recognition to loosely adherent cell clusters and ultimately, to strongly compacted groups of cells in colonies. Recent studies have described distinct roles for intermolecular clustering of cadherins as well as interactions of cadherin with the actin cytoskeleton in establishing cell-cell adhesion. Integrating cytomechanical roles of cadherin-mediated adhesion will lead to a greater understanding of how cadherins regulate tissue morphogenesis.

• Tamura K, Shan WS, Hendrickson WA, Colman DR, Shapiro L
• Structure-function analysis of cell adhesion by neural (N-) cadherin.
• Neuron. 1998; 20: 1153-63
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• To investigate the possible biological function of the lateral "strand dimer" observed in crystal structures of a D1 domain extracellular fragment from N-cadherin, we have undertaken site-directed mutagenesis studies of this molecule. Mutation of most residues important in the strand dimer interface abolish the ability of N-cadherin to mediate cell adhesion. Mutation of an analogous central residue (Trp-2) in E-cadherin also abrogates the adhesive capacity of that molecule. We also determined the crystal structure of a Ca2+-complexed two-domain fragment from N-cadherin. This structure, like its E-cadherin counterpart, does not adopt the strand dimer conformation. This suggests the possibility that classical cadherins might stably exist in both dimeric and monomeric forms. Data from several laboratories imply that lateral dimerization or clustering of cadherins may increase their adhesivity. We suggest the possibility that the strand dimer may play a role in this activation.

• Yap AS
• The morphogenetic role of cadherin cell adhesion molecules in human cancer: a thematic review.
• Cancer Invest. 1998; 16: 252-61

• Ozawa M, Kemler R
• The membrane-proximal region of the E-cadherin cytoplasmic domain prevents dimerization and negatively regulates adhesion activity.
• J Cell Biol. 1998; 142: 1605-13
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• Cadherins are transmembrane glycoproteins involved in Ca2+-dependent cell-cell adhesion. Deletion of the COOH-terminal residues of the E-cadherin cytoplasmic domain has been shown to abolish its cell adhesive activity, which has been ascribed to the failure of the deletion mutants to associate with catenins. Based on our present results, this concept needs revision. As was reported previously, leukemia cells (K562) expressing E-cadherin with COOH-terminal deletion of 37 or 71 amino acid residues showed almost no aggregation. Cells expressing E-cadherin with further deletion of 144 or 151 amino acid residues, which eliminates the membrane-proximal region of the cytoplasmic domain, showed E-cadherin-dependent aggregation. Thus, deletion of the membrane-proximal region results in activation of the nonfunctional E-cadherin polypeptides. However, these cells did not show compaction. Chemical cross-linking revealed that the activated E-cadherin polypeptides can be cross-linked to a dimer on the surface of cells, whereas the inactive polypeptides, as well as the wild-type E-cadherin polypeptide containing the membrane-proximal region, can not. Therefore, the membrane-proximal region participates in regulation of the adhesive activity by preventing lateral dimerization of the extracellular domain.

• Suzuki ST
• [Adhesion complex and biological roles of cadherins]
• Seikagaku. 1997; 69: 1269-71

• Shibata T, Shimoyama Y, Gotoh M, Hirohashi S
• Identification of human cadherin-14, a novel neurally specific type II cadherin, by protein interaction cloning.
• J Biol Chem. 1997; 272: 5236-40
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• Cadherins, a family of Ca2+-dependent cell-cell adhesion molecules, mediate neural cell-cell interactions and may play important roles in neural development. By searching for molecules that interact with beta-catenin, a cytoplasmic regulator of cadherins, we have identified a new member of the cadherin family, which we named human cadherin-14. Cadherin-14 had high amino acid sequence homology with the type II subgroup of cadherins and was broadly expressed in the central nervous system. Cadherin-14 is a novel neurally specific cell-cell adhesion molecule and may regulate neural morphogenesis.

• Kreft B et al.
• LI-cadherin-mediated cell-cell adhesion does not require cytoplasmic interactions.
• J Cell Biol. 1997; 136: 1109-21
• Display abstract

• The adhesive function of classical cadherins depends on the association with cytoplasmic proteins, termed catenins, which serve as a link between cadherins and the actin cytoskeleton. LI-cadherin, a structurally different member of the cadherin family, mediates Ca2+-dependent cell-cell adhesion, although its markedly short cytoplasmic domain exhibits no homology to this highly conserved region of classical cadherins. We now examined whether the adhesive function of LI-cadherin depends on the interaction with catenins, the actin cytoskeleton or other cytoplasmic components. In contrast to classical cadherins, LI-cadherin, when expressed in mouse L cells, was neither associated with catenins nor did it induce an upregulation of beta-catenin. Consistent with these findings, LI-cadherin was not resistant to detergent extraction and did not induce a reorganization of the actin cytoskeleton. However, LI-cadherin was still able to mediate Ca2+-dependent cell-cell adhesion. To analyze whether this function requires any interaction with proteins other than catenins, a glycosyl phosphatidylinositol-anchored form of LI-cadherin (LI-cadherin(GPI)) was constructed and expressed in Drosophila S2 cells. The mutant protein was able to induce Ca2+-dependent, homophilic cell-cell adhesion, and its adhesive properties were indistinguishable from those of wild type LI-cadherin. These findings indicate that the adhesive function of LI-cadherin is independent of any interaction with cytoplasmic components, and consequently should not be sensitive to regulatory mechanisms affecting the binding of classical cadherins to catenins and to the cytoskeleton. Thus, we postulate that the adhesive function of LI-cadherin is complementary to that of coexpressed classical cadherins ensuring cell-cell contacts even under conditions that downregulate the function of classical cadherins.

• Miller JR, McClay DR
• Characterization of the role of cadherin in regulating cell adhesion during sea urchin development.
• Dev Biol. 1997; 192: 323-39
• Display abstract

• During development, the modulation of cadherin adhesive function is proposed to control various morphogenetic events including epithelial-mesenchymal conversions and tubulogenesis, although the mechanisms responsible for regulating cadherin activity during these events remain unclear. In order to gain insights into the regulation of cadherin function during morphogenesis, we utilized the sea urchin embryo as a model system to study the regulation of cadherin localization during epithelial-mesenchymal conversion and convergent-extension movements. Polyclonal antibodies raised against the cytoplasmic domain of a cloned sea urchin cadherin recognize three major polypeptides of M(r) 320, 140, and 125 kDa and specifically stain adherens junctions, and to a lesser extent, lateral membrane domains in all epithelial tissues of the embryo. Analysis of embryos during gastrulation demonstrates that changes in cadherin localization are observed in cells undergoing an epithelial-mesenchymal conversion. Ingression of primary mesenchyme cells is accompanied by the rapid loss of junctional cadherin staining and the coincident accumulation of cadherin in intracellular organelles. These data are consistent with the idea that the deadhesion of mesenchymal cells from neighboring epithelial cells involves the regulated endocytosis of cell surface cadherin molecules. Conversely, neither cadherin abundance nor localization is altered in cells of the gut which undergo convergent-extension movements during the formation of the archenteron. This observation indicates that these movements do not require the loss of junctional cadherin molecules. Instead, the necessary balance between adhesion and motility may be achieved by regulating the expression of different subtypes of cadherin molecules or modifying interactions between cadherins and catenins, proteins that bind the cytoplasmic domain of cadherin and are necessary for cadherin adhesive function. To address cadherin function at the molecular level, we used a partial cDNA representing the conserved cytoplasmic domain to identify a novel cadherin molecule in the sea urchin Lytechinus variegatus. The deduced amino acid sequence of LvG-cadherin (for Goliath-cadherin) predicts that it is a transmembrane protein with an apparent relative molecular mass of 303 kDa. The cytoplasmic domain shows significant sequence identity to that of vertebrate classic cadherins. However, the extracellular domain is distinguished from its vertebrate counterparts by both an increased number of cadherin-specific repeats and the presence of four EGF-like repeats proximal to the transmembrane domain. Taken together, these data are consistent with the hypothesis that the sea urchin possesses several cadherins, including a novel member of the cadherin family, and that the dynamic regulation of cadherin localization plays a role in epithelial to mesenchymal conversions during gastrulation.

• Suzuki ST
• [Cadherin superfamily: structural and functional properties of cadherins]
• Tanpakushitsu Kakusan Koso. 1997; 42: 1669-73

• Leahy DJ
• Implications of atomic-resolution structures for cell adhesion.
• Annu Rev Cell Dev Biol. 1997; 13: 363-93
• Display abstract

• Molecules involved in cell adhesion processes are often both structurally and functionally modular, with subdomains that are members of large protein families. Recently, high-resolution structures have been determined for representative members of many of these families including fragments of integrins, cadherins, fibronectin-like domains, and immunoglobulin-like domains. These structures have enhanced our understanding of cell adhesion processes at several levels. In almost all cases, ligand-binding sites have been visualized and provide insight into how these molecules mediate biologically important interactions. Metal-binding sites have been identified and characterized, allowing assessment of the role of bound ions in cell adhesion processes. Many of these structures serve as templates for modeling homologous domains in other proteins or, when the structure of a fragment consisting of more than one domain is determined, the structure of multidomain arrays of homologous domains. Knowledge of atomic structure also allows rational design of drugs that either mimic or target specific binding sites. In many cases, high-resolution structures have revealed unexpected relationships that pose questions about the evolutionary origin of specific domains. This review briefly describes several recently determined structures of cell adhesion molecules, summarizes some of the main results of each structure, and highlights common features of different systems.

• Aberle H, Schwartz H, Kemler R
• Cadherin-catenin complex: protein interactions and their implications for cadherin function.
• J Cell Biochem. 1996; 61: 514-23
• Display abstract

• Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multicellular organisms. In epithelial cells, E-cadherin represents a key molecule in the establishment and stabilization of cellular junctions. On the cellular level, E-cadherin is concentrated at the adherens junction and interacts homophilically with E-cadherin molecules of adjacent cells. Significant progress has been made in understanding the extra- and intracellular interactions of E-cadherin. Recent success in solving the three-dimensional structure of an extracellular cadherin domain provides a structural basis for understanding the homophilic interaction mechanism and the calcium requirement of cadherins. According to the crystal structure, individual cadherin molecules cooperate to form a linear cell adhesion zipper. The intracellular anchorage of cadherins is regulated by the dynamic association with cytoplasmic proteins, termed catenins. The cytoplasmic domain of E-cadherin is complexed with either beta-catenin or plakoglobin (gamma-catenin). Beta-catenin and plakoglobin bind directly to alpha-catenin, giving rise to two distinct cadherin-catenin complexes (CCC). Alpha-catenin is thought to link both CCC's to actin filaments. The anchorage of cadherins to the cytoskeleton appears to be regulated by tyrosine phosphorylation. Phosphorylation-induced junctional disassembly targets the catenins, indicating that catenins are components of signal transduction pathways. The unexpected association of catenins with the product of the tumor suppressor gene APC has led to the discovery of a second, cadherin-independent catenin complex. Two separate catenin complexes are therefore involved in the cross-talk between cell adhesion and signal transduction. In this review we focus on protein interactions regulating the molecular architecture and function of the CCC. In the light of a fundamental role of the CCC during mammalian development and tissue morphogenesis, we also discuss the phenotypes of embryos lacking E-cadherin or beta-catenin.

• van der Linden PJ
• Cell adhesion, cell adhesion molecules and their functional role in the human endometrium.
• Early Pregnancy. 1996; 2: 5-14
• Display abstract

• In summary, cadherins are important determinants of tissue morphology. They play a major role in the maintenance of intercellular junctions in normal epithelial cells in most organs. Cadherin expression is found to be perturbed in human invasive carcinoma. Cadherins are probably crucial for many other morphogenetic processes which involve selective cell adhesion or detachment. Expression of integrins allows binding of endometrial cells to various ligands (fibronectin, laminin, collagens) and hence adds to the preservation of the architectural integrity of endometrium. Regulation of adhesion-molecule expression probably contributes to the invasive behavior of cytotrophoblast, both in physiological and pathophysiological conditions. The integrin expression by the endometrium seems to be a dynamic process, many details of which still remain to be elucidated.

• Shibamoto S
• [Cell adhesion mediated by cadherin-catenin machinery and signal transduction]
• Seikagaku. 1996; 68: 1650-3

• Witcher LL et al.
• Desmosomal cadherin binding domains of plakoglobin.
• J Biol Chem. 1996; 271: 10904-9
• Display abstract

• Plakoglobin is a major component of both desmosomes and adherens junctions. At these sites it binds to the cytoplasmic domains of cadherin cell-cell adhesion proteins and regulates their adhesive and cytoskeletal binding functions. Plakoglobin also forms distinct cytosolic protein complexes that function in pathways of tumor suppression and cell fate determination. Recent studies in Xenopus suggest that cadherins inhibit the signaling functions of plakoglobin presumably by sequestering this protein at the membrane and depleting its cytosolic pool. To understand the reciprocal regulation between desmosomal cadherins (desmoglein and desmocollin) and plakoglobin, we have sought to identify the binding domains involved in the formation of these protein complexes. Plakoglobin comprises 13 central repeats flanked by amino-terminal and carboxyl-terminal domains. Our results show that repeats 1-4 are involved in binding desmoglein-1. In contrast, the interaction of plakoglobin with desmocollin-1a is sensitive to deletion of either end of the central repeat domain. The binding sites for two adherens junction components, alpha-catenin and classical cadherins, overlap these sites. Competition among these proteins for binding sites on plakoglobin may therefore account for the distinct composition of adherens junctions and desmosomes.

• Lutz KL, Szabo LA, Thompson DL, Siahaan TJ
• Antibody recognition of peptide sequences from the cell-cell adhesion proteins: N- and E-cadherins.
• Pept Res. 1996; 9: 233-9
• Display abstract

• Intercellular junctions present a formidable challenge for the paracellular delivery of drugs. Cadherins are calcium-dependent cell-cell adhesion molecules, which are responsible for the formation and regulation of these junctions. Anti-E-cadherin monoclonal antibody can bind to E-cadherin (uvomorulin) and inhibit cell-cell adhesion through the inhibition of cadherin-cadherin interactions. The objective of this study was to utilize this monoclonal anti-E-cadherin antibody to map the extracellular domains of E- and N-cadherin. This was accomplished by using two different enzyme-linked immunosorbent assays (ELISAs), a regular indirect ELISA and an immobilized-peptide ELISA. Two peptides from each extracellular domain were recognized by this anti-E-cadherin antibody. By mapping the extracellular domains of cadherins, peptides that have discrete roles in cell-cell adhesion can be identified. This will aid in the design of synthetic peptides that can modulate intercellular junctions to improve drug delivery.

• Jones EY
• Three-dimensional structure of cell adhesion molecules.
• Curr Opin Cell Biol. 1996; 8: 602-8
• Display abstract

• Recent structural data have provided insights into various forms of specific cell adhesion interactions, including both protein-protein and protein-glycoconjugate recognition events. The major advances have been made in the structural characterization of cadherin-cadherin and integrin-ligand mediated adhesion.

• Marrs JA, Nelson WJ
• Cadherin cell adhesion molecules in differentiation and embryogenesis.
• Int Rev Cytol. 1996; 165: 159-205
• Display abstract

• The cadherin gene superfamily of calcium-dependent cell-cell adhesion molecules contains more than 40 members. We summarize functions attributed to these proteins, especially their roles in cellular differentiation and embryogenesis. We also describe hierarchies of protein-protein interactions between cadherins and cadherin-associated proteins (catenins). Several signal transduction pathways converge on, and diverge from, the cadherin/catenin complex to regulate its function; we speculate on roles of these signaling processes for cell structure and function. This review provides a framework for interpretation of developmental functions of cadherin cell adhesion molecules.

• Karecla PI, Green SJ, Bowden SJ, Coadwell J, Kilshaw PJ
• Identification of a binding site for integrin alphaEbeta7 in the N-terminal domain of E-cadherin.
• J Biol Chem. 1996; 271: 30909-15
• Display abstract

• The integrin alphaEbeta7, which is predominantly expressed on mucosal T lymphocytes, has recently been shown to recognize the cell adhesion molecule, E-cadherin, on epithelial cells. We have carried out mutations on E-cadherin, involving domain deletions as well as substitutions of specific amino acids, in order to identify the sites recognized by the integrin. Binding of alphaEbeta7 required the presence of the first two N-terminal domains of E-cadherin. Deletion of extracellular domains 3 and 4 or truncation of the cytoplasmic domain of E-cadherin had no consequence on integrin binding. Substitution of a glutamic acid in the BC loop of the Ig structure of the fist, N-terminal, domain of E-cadherin abrogated binding of alphaEbeta7. This mutation did not appear to affect the conformation of the domain nor the pattern of expression of E-cadherin on the cell surface. Synthetic peptides encompassing the first domain of E-cadherin had very little inhibitory effect on the interaction with alphaEbeta7. Our results highlight structural dissimilarities between recognition of E-cadherin by alphaEbeta7 and recognition of other members of the IgSF by integrins and show that the heterophilic (integrin binding) and homophilic sites in the N-terminal domain of E-cadherin are distinct.

• Thiery JP
• The saga of adhesion molecules.
• J Cell Biochem. 1996; 61: 489-92

• Suzuki ST
• Structural and functional diversity of cadherin superfamily: are new members of cadherin superfamily involved in signal transduction pathway?
• J Cell Biochem. 1996; 61: 531-42
• Display abstract

• A large number of cadherins and cadherin-related proteins are expressed in different tissues of a variety of multicellular organisms. These proteins share one property: their extracellular domains consist of multiple repeats of a cadherin-specific motif. A recent structure study has shown that the cadherin repeats roughly corresponding to the folding unit of the extracellular domains. The members of the cadherin superfamily are roughly classified into two groups, classical type cadherins proteins and protocadherin type according to their structural properties. These proteins appear to be derived from a common ancestor that might have cadherin repeats similar to those of the current protocadherins, and to have common functional properties. Among various cadherins, E-cadherin was the first to be identified as a Ca(2+)-dependent homophilic adhesion protein. Recent knockout mice experiments have proven its biological role, but there are still several puzzling unsolved properties of the cell adhesion activity. Other members of cadherin superfamily show divergent properties and many lack some of the expected properties of cell adhesion protein. Since recent studies of various adhesion proteins reveal that they are involved in different signal transduction pathways, the idea that the new members of cadherin superfamily may participate in more general cell-cell interaction processes including signal transduction is an intriguing hypothesis. The cadherin superfamily is structurally divergent and possibly functionally divergent as well.

• Overduin M, Tong KI, Kay CM, Ikura M
• 1H, 15N and 13C resonance assignments and monomeric structure of the amino-terminal extracellular domain of epithelial cadherin.
• J Biomol NMR. 1996; 7: 173-89
• Display abstract

• E-cadherin is a transmembrane protein that provides Ca(2+)-dependent cell adhesion to epithelial cells. The large majority of the 1H, 15N, 13C and 13CO resonances of a 146-amino acid polypeptide from epithelial (E-) cadherin have been assigned using multidimensional NMR spectroscopy. The structure of the amino-terminal 100 amino acids, corresponding to the first extracellular repeat of E-cadherin [Overduin et al. (1995) Science, 267, 386-389], has been refined. The monomeric state of this isolated domain is demonstrated by light scattering and sedimentation analysis. Seven beta-strands and two short helices were identified by patterns of NOE cross-peaks, vicinal coupling constants and chemical shift indices. A novel structural motif termed a quasi-beta-helix found in the crystal structure of a neural (N-) cadherin domain [Shapiro et al. (1995) Nature, 374, 327-337] is characterized in detail for the first time by NMR. Slowly exchanging amides were concentrated in the beta-sheet region and quasi-beta-helix. The beta-barrel fold of the cadherin domain is topologically similar to the immunoglobulin fold. Comparison of this solution structure to the crystallized dimers of the N-terminal pair of E-cadherin domains [Nagar et al. (1996) Nature, 380, 360-364] and of the homologous single domain of N-cadherin reveals a conserved cadherin fold with minor structural differences, which can be accounted for by differences in metal ligation and oligomeric state.

• Thomsen NK et al.
• The three-dimensional structure of the first domain of neural cell adhesion molecule.
• Nat Struct Biol. 1996; 3: 581-5

• Vaughn DE, Bjorkman PJ
• The (Greek) key to structures of neural adhesion molecules.
• Neuron. 1996; 16: 261-73

• Nagar B, Overduin M, Ikura M, Rini JM
• Structural basis of calcium-induced E-cadherin rigidification and dimerization.
• Nature. 1996; 380: 360-4
• Display abstract

• The cadherins mediate cell adhesion and play a fundamental role in normal development. They participate in the maintenance of proper cell-cell contacts: for example, reduced levels of epithelial cadherin (E-cadherin) correlate with increased invasiveness in many human tumour cell types. The cadherins typically consist of five tandemly repeated extracellular domains, a single membrane-spanning segment and a cytoplasmic region. The N-terminal extracellular domains mediate cell-cell contact while the cytoplasmic region interacts with the cytoskeleton through the catenins. Cadherins depend on calcium for their function: removal of calcium abolishes adhesive activity, renders cadherins vulnerable to proteases (reviewed in ref. 4) and, in E-cadherin, induces a dramatic reversible conformational change in the entire extracellular region. We report here the X-ray crystal structure at 2.0 A resolution of the two N-terminal extracellular domains of E-cadherin in the presence of calcium. The structure reveals a two-fold symmetric dimer, each molecule of which binds a contiguous array of three bridged calcium ions. Not only do the bound calcium ions linearize and rigidify the molecule, they promote dimerization. Although the N-terminal domain of each molecule in the dimer is aligned in a parallel orientation, the interactions between them differ significantly from those found in the neural cadherin (N-cadherin) N-terminal domain (NCD1) structure. The E-cadherin dual-domain structure reported here defines the role played by calcium in the cadherin-mediated formation and maintenance of solid tissues.

• Roh JY, Stanley JR
• Intracellular domain of desmoglein 3 (pemphigus vulgaris antigen) confers adhesive function on the extracellular domain of E-cadherin without binding catenins.
• J Cell Biol. 1995; 128: 939-47
• Display abstract

• For the extracellular (EC) domain of E-cadherin to function in homophilic adhesion it is thought that its intracytoplasmic (IC) domain must bind alpha- and beta-catenins, which link it to the actin cytoskeleton. However, the IC domain of pemphigus vulgaris antigen (PVA or Dsg3), which is in the desmoglein subfamily of the cadherin gene superfamily, does not bind alpha- or beta-catenins. Because desmogleins have also been predicted to function in the cell adhesion of desmosomes, we speculated that the PVA IC domain might be able to act in a novel way in conferring adhesive function on the EC domain of cadherins. To test this hypothesis we studied aggregation of mouse fibroblast L cell clones that expressed chimeric cDNAs encoding the EC domain of E-cadherin with various IC domains. We show here that the full IC domain of PVA as well as an IC subdomain containing only 40 amino acids of the PVA intracellular anchor (IA) region confer adhesive function on the E-cadherin EC domain without catenin-like associations with cytoplasmic molecules or fractionation with the cell cytoskeleton. This IA region subdomain is evolutionarily conserved in desmogleins, but not classical cadherins. These findings suggest an important cell biologic function for the IA region of desmogleins and demonstrate that strong cytoplasmic interactions are not absolutely necessary for E-cadherin-mediated adhesion.

• Koike T, Hamaguchi M
• [The structure and function of cadherins and their pathophysiological roles in diseases]
• Nippon Rinsho. 1995; 53: 1578-84
• Display abstract

• Cadherins are a family of Ca(2+)-dependent cell adhesion molecules that mediate cell adhesion by homophilic interaction and play critical role in multicellular organ formation. Recent progress revealed the three-dimensional structure of extracellular cadherin repeats that made great progress in the study of cell adhesion by cadherins. The perturbation of cadherin function in transformed cells results in inhibition of cell-cell adhesion, that appears to promote metastasis and invasiveness of tumor cells. Expression as well as modifications of catenins, which link cadherins to cytoskeletons, have crucial effects on this purturbation mechanisms. Tyrosine phosphorylation of cadherin catenin complex may be the important regulatory mechanism.

• Lasky LA
• From sticky zippers to morphology.
• Nat Struct Biol. 1995; 2: 258-61

• Takeichi M
• Morphogenetic roles of classic cadherins.
• Curr Opin Cell Biol. 1995; 7: 619-27
• Display abstract

• Classic cadherins, which are known to be crucial for homotypic cell-cell adhesion, have been found to be present not only in vertebrate but also in invertebrate species. Their three-dimensional structures, novel functions, and novel expression patterns were reported recently. These have been important steps towards a deeper understanding of the morphogenetic roles of this family of molecules.

• Prieto AL, Crossin KL
• Cell-cell adhesion molecules in epithelial-mesenchymal transformations.
• Acta Anat (Basel). 1995; 154: 21-33
• Display abstract

• The functional units in most inductive and morphogenetic processes in the embryo are not single cells, but rather collectives of interacting cells that give rise to the tissues and organs. Cell adhesion molecules (CAMs) are involved in defining cell collectives and their borders as they interact during inductive events in morphogenesis. The expression patterns of CAMs are highly dynamic and changes are known to occur during epithelial-mesenchymal transformations. Alterations in CAM expression are correlated with changes in morphology. Conversely, experimentally induced changes in morphology result in changes in CAM expression. The structure, function, distribution, and control of CAM gene expression are presented in this review, and discussed with regard to their importance to normal developmental processes, particularly epithelial-mesenchymal transformations.

• Murphy-Erdosh C, Yoshida CK, Paradies N, Reichardt LF
• The cadherin-binding specificities of B-cadherin and LCAM.
• J Cell Biol. 1995; 129: 1379-90
• Display abstract

• The cadherin family of calcium-dependent cell adhesion molecules plays an important part in the organization of cell adhesion and tissue segregation during development. The expression pattern and the binding specificity of each cadherin are of principal importance for its role in morphogenesis. B-Cadherin and LCAM, two chicken cadherins, have similar, but not identical, spatial and temporal patterns of expression. To examine the possibility that they might bind to one another in a heterophilic manner, we generated, by cDNA transfection, L-cell lines that express LCAM or B-cadherin. We then examined the abilities of these cells to coaggregate with each other and with other cadherin-expressing cells in short-term aggregation assays. The B-cadherin- and the LCAM-expressing cell lines segregate from P-, N-, or R-cadherin-expressing cells. B-cadherin- and LCAM-expressing cell lines, however, appear to be completely miscible, forming large mixed aggregates. Chick B-cadherin and murine E-cadherin also form mixed aggregates, indistinguishable from homophilic aggregates. Murine E-cadherin and chick LCAM coaggregate less completely, suggesting that the heterophilic interactions of these two cell lines are weak relative to homophilic interactions. These data suggest that heterophilic interactions between B-cadherin and LCAM are important during avian morphogenesis and help identify the amino acids in the binding domain that determine cadherin specificity.

• Wagner G
• E-cadherin: a distant member of the immunoglobulin superfamily.
• Science. 1995; 267: 342-342

• Weis WI
• Cadherin structure: a revealing zipper.
• Structure. 1995; 3: 425-7
• Display abstract

• The crystal structure of the N-terminal domain of neural cadherin provides the first atomic-level picture of interacting cell-adhesion molecules, and suggests a mechanism for assembly and disassembly of intercellular adhesion zones.

• Murphy-Erdosh C, Napolitano EW, Reichardt LF
• The expression of B-cadherin during embryonic chick development.
• Dev Biol. 1994; 161: 107-25
• Display abstract

• Cadherins compose a family of calcium-dependent cell adhesion molecules that are involved in the segregation of differentiating tissues during development. Each cadherin has a unique spatial and temporal pattern of expression. As has been observed for other cadherins, B-cadherin, when expressed in mouse L929 fibroblasts, confers upon them a calcium-dependent cell aggregation activity. A monoclonal antibody to B-cadherin was isolated and used to determine the pattern of expression of B-cadherin in the developing chick embryo. Antibody staining and in situ hybridization reveal that B-cadherin protein and mRNA are found in diverse epithelia derived from each of the three primary germ layers, where their expression is strikingly regulated during differentiation. In some instances, the regional distribution of B-cadherin within a tissue reflects the distinct functional regions of the tissue. Patterns of staining are similar to, but distinct from, those seen with anti-LCAM antibodies. Although there are many examples where B-cadherin and LCAM are coexpressed, there are also distinctive regional differences.

• Edelman GM
• Adhesion and counteradhesion: morphogenetic functions of the cell surface.
• Prog Brain Res. 1994; 101: 1-14

• Behrens J
• Cadherins as determinants of tissue morphology and suppressors of invasion.
• Acta Anat (Basel). 1994; 149: 165-9
• Display abstract

• During the past years cell-cell adhesion molecules of the cadherin family have been recognized as major regulators of such diverse processes as normal morphogenesis and tumor metastasis. Since the list of new cadherin family members is constantly growing, the functional spectrum of these proteins is likely to broaden. This review will describe our current knowledge on cadherins and point out new aspects of cadherin function and regulation.

• Berndorff D et al.
• Liver-intestine cadherin: molecular cloning and characterization of a novel Ca(2+)-dependent cell adhesion molecule expressed in liver and intestine.
• J Cell Biol. 1994; 125: 1353-69
• Display abstract

• A novel member of the cadherin family of cell adhesion molecules has been characterized by cloning from rat liver, sequencing of the corresponding cDNA, and functional analysis after heterologous expression in nonadhesive S2 cells. cDNA clones were isolated using a polyclonal antibody inhibiting Ca(2+)-dependent intercellular adhesion of hepatoma cells. As inferred from the deduced amino acid sequence, the novel molecule has homologies with E-, P-, and N-cadherins, but differs from these classical cadherins in four characteristics. Its extracellular domain is composed of five homologous repeated domains instead of four characteristic for the classical cadherins. Four of the five domains are characterized by the sequence motifs DXNDN and DXD or modifications thereof representing putative Ca(2+)-binding sites of classical cadherins. In its NH2-terminal region, this cadherin lacks both the precursor segment and the endogenous protease cleavage site RXKR found in classical cadherins. In the extracellular EC1 domain, the novel cadherin contains an AAL sequence in place of the HAV sequence motif representing the common cell adhesion recognition sequence of E-, P-, and N-cadherin. In contrast to the conserved cytoplasmic domain of classical cadherins with a length of 150-160 amino acid residues, that of the novel cadherin has only 18 amino acids. Examination of transfected S2 cells showed that despite these structural differences, this cadherin mediates intercellular adhesion in a Ca(2+)-dependent manner. The novel cadherin is solely expressed in liver and intestine and was, hence, assigned the name LI-cadherin. In these tissues, LI-cadherin is localized to the basolateral domain of hepatocytes and enterocytes. These results suggest that LI-cadherin represents a new cadherin subtype and may have a role in the morphological organization of liver and intestine.

• Muller HA et al.
• Xenopus cadherins: the maternal pool comprises distinguishable members of the family.
• Mech Dev. 1994; 47: 213-23
• Display abstract

• Three maternal cadherins have been reported to occur in the pregastrula Xenopus embryo. EP- and XB-cadherin are distinguished by their distinct cDNA sequences. U-cadherin has been characterized by its reaction with a specific monoclonal antibody (mAb 6D5). Thus far, lack of specific probes that discriminate between these molecules has prevented their identification as distinct cadherins. We now demonstrate by means of RNase protection assays that both EP- and XB-cadherin mRNAs are present in oocytes and mature eggs. By use of the Xenopus cadherin proteins expressed in mammalian cell lines, we find that mAb 6D5 crossreacts with XB-cadherin, but not with EP-cadherin. The major fraction of the maternal cadherins does not contain the 6D5 epitope and probably represents EP-cadherin. A minor fraction carries the 6D5 epitope indicative for the XB- and U-type of cadherins. We have termed this fraction XB/U-cadherin. The function of maternal cadherins was examined by in vitro cell adhesion assays. A newly developed antiserum with a broad specificity for various Xenopus cadherins efficiently blocks all calcium dependent cell adhesion in the early embryo. We conclude that the maternal cadherins play a central role in interblastomere adhesion in the early embryo and comprise at least two discrete cadherin forms, EP- and XB/U-cadherin.

• Fujimori T, Takeichi M
• Disruption of epithelial cell-cell adhesion by exogenous expression of a mutated nonfunctional N-cadherin.
• Mol Biol Cell. 1993; 4: 37-47
• Display abstract

• Cadherins, a family of transmembrane cell-cell adhesion receptors, require interactions with the cytoskeleton for normal function. To assess the mechanisms of these interactions, we studied the effect of exogenous expression of a mutant N-cadherin, cN390 delta; on epithelial cell-cell adhesion. The intracellular domain of cN390 delta was intact but its extracellular domain was largely deleted so that this molecule was not functional for cell adhesion. cDNA of cN390 delta was attached to the metallothionein promoter, and introduced into the keratinocyte line PAM212 expressing endogenous E- and P-cadherin. When the expression of cN390 delta was induced by Zn2+, cadherin-dependent adhesion of the transfected cells was inhibited, resulting in the dispersion of cell colonies, although their contacts were maintained under high cell density conditions. In these cultures, cN390 delta was expressed not only on the free surfaces of the cells but also at cell-cell junctions. The endogenous cadherins were concentrated at cell-cell junctions under normal conditions. As a result of cN390 delta expression, however, the endogenous cadherins localizing at the cell-cell junctions were largely diminished, suggesting that these molecules were replaced by the mutant molecules at these sites. As a control, we transfected the same cell line with cDNA of a truncated form of N-cadherin cadherin whose intracellular C terminus had been deleted leaving the extracellular domain intact. This molecule had no effect on cell-cell adhesion, nor did it localize to cell-cell contact sites. We also found that the association of the endogenous cadherins with alpha- and beta-catenins and plakoglobin was not affected by the expression of cN390 delta, which also formed a complex with these molecules, suggesting that no competition occurred between the endogenous and exogenous cadherins for these cytoplasmic proteins. These and other additional results suggest that the nonfunctional cadherins whose intracellular domain is intact occupy the sites where the endogenous cadherins should localize, through interactions with the cytoskeleton, and inhibit the cadherin adhesion system.

• Ozawa M
• [Catenins: the proteins associated with the cytoplasmic domain of cadherins]
• Seikagaku. 1993; 65: 462-5

• Figarella-Branger D, Pellissier JF, Rougon G
• [Cell adhesion molecules. Structure, role in metastatic processes and expression in human solid tumors]
• Ann Pathol. 1993; 13: 296-305

• Nagafuchi A, Tsukita S, Takeichi M
• Transmembrane control of cadherin-mediated cell-cell adhesion.
• Semin Cell Biol. 1993; 4: 175-81
• Display abstract

• The cadherin family of cell-cell adhesion molecules plays a central role in organization of cells into multicellular structures. An important feature of the action of cadherins is that they form a complex with cytoskeletal proteins, and the formation of this complex is crucial for their adhesive function. Cadherin-mediated cell adhesion is thus controlled through the interaction with cytoplasmic proteins, and, for such control, phosphorylation of these proteins and also cadherins themselves might be involved. This regulatory mechanism of cell adhesion is perhaps fundamental to a variety of morphogenetic processes.

• Nathke IS, Hinck LE, Nelson WJ
• Epithelial cell adhesion and development of cell surface polarity: possible mechanisms for modulation of cadherin function, organization and distribution.
• J Cell Sci Suppl. 1993; 17: 139-45
• Display abstract

• Epithelial cell adhesion is principally regulated by calcium-dependent cell adhesion proteins, termed cadherins. Recent studies indicate that cadherin function is modulated by a class of proteins, termed catenins, that bind to the cytoplasmic domain of cadherin. Here we review the evidence that catenins regulate cadherin function in cell-cell adhesion, and discuss their role in initiating cell surface polarity in epithelial cells.

• Dalseg AM, Gaardsvoll H, Bock E
• Molecular biology of cadherins in the nervous system.
• Mol Neurobiol. 1993; 7: 207-28
• Display abstract

• Cadherins are cell-cell adhesion molecules belonging to the Ca(2+)-dependent cadherin superfamily. In the last few years the number of cadherins identified in the nervous system has increased considerably. Cadherins are integral membrane glycoproteins. They are structurally closely related and interspecies homologies are high. The function is mediated through a homophilic binding mechanism, and intracellular proteins, directly or indirectly connected to the cadherins and the cytoskeleton, are necessary for cadherin activity. Cadherins have been implicated in segregation and aggregation of tissues at early developmental stages and in growth and guidance of axons during nervous system development. These functions are modified by changes in type(s) and amount of cadherins expressed at different developmental stages. The regulatory elements guiding cadherin expression are currently being elucidated.

• Grunwald GB
• The structural and functional analysis of cadherin calcium-dependent cell adhesion molecules.
• Curr Opin Cell Biol. 1993; 5: 797-805
• Display abstract

• During the past year considerable progress has been made in our understanding of cadherin structure and function. Recent research has concentrated on several aspects of the cell and molecular biology of cadherins, including genomic organization, cytoskeletal interactions, regulation of expression and function by post-translational modifications, differential expression during embryonic development, and the emerging role of cadherin misexpression and malfunction in pathogenesis.

• Tsukita S
• [Regulation of cadherin-based cell adhesion and metastasis]
• Gan To Kagaku Ryoho. 1993; 20: 348-52
• Display abstract

• Cadherins are a family of transmembrane glycoproteins which are responsible for calcium-dependent cell-cell adhesion. At least two types of proteins called alpha- and beta-catenin are known to be closely associated with the cytoplasmic domain of cadherin molecules and to play a crucial role in the regulation of cadherin cell adhesion function. Sequence analyses of cDNAs encoding these catenins have revealed that alpha- and beta-catenins have a similarity to vinculin and Drosophila armadillo protein, respectively. The possible involvement of these catenin molecules in the molecular mechanism of human cancer invasion and metastasis is discussed.

• Kintner C
• Regulation of embryonic cell adhesion by the cadherin cytoplasmic domain.
• Cell. 1992; 69: 225-36
• Display abstract

• Differential adhesion between embryonic cells has been proposed to be mediated by a family of closely related glycoproteins called the cadherins. The cadherins mediate adhesion in part through an interaction between the cadherin cytoplasmic domain and intracellular proteins, called the catenins. To determine whether these interactions could regulate cadherin function in embryos, a form of N-cadherin was generated that lacks an extracellular domain. Expression of this mutant in Xenopus embryos causes a dramatic inhibition of cell adhesion. Analysis of the mutant phenotype shows that at least two regions of the N-cadherin cytoplasmic domain can inhibit adhesion and that the mutant cadherin can inhibit catenin binding to E-cadherin. These results suggest that cadherin-mediated adhesion can be regulated by cytoplasmic interactions and that this regulation may contribute to morphogenesis when emerging tissues coexpress several cadherin types.

• Pouliot Y
• Phylogenetic analysis of the cadherin superfamily.
• Bioessays. 1992; 14: 743-8
• Display abstract

• Cadherins are a multigene family of proteins which mediate homophilic calcium-dependent cell adhesion and are thought to play an important role in morphogenesis by mediating specific intercellular adhesion. Different lines of experimental evidence have recently indicated that the site responsible for mediating adhesive interactions is localized to the first extracellular domain of cadherin. Based upon an analysis of the sequence of this domain, I show that cadherins can be classified into three groups with distinct structural features. Furthermore, using this sequence information a phylogenetic tree relating the known cadherins was assembled. This is the first such tree to be published for the cadherins. One cadherin subtype, neural cadherin (N-cadherin), shows very little sequence divergence between species, whereas all other cadherin subtypes show more substantial divergence, suggesting that selective pressure upon this domain may be greater for N-cadherin than for other cadherins. Phylogenetic analysis also suggests that the gene duplications which established the main branches leading to the different cadherin subtypes occurred very early in their history. These duplications set the stage for the diversified superfamily we now observe.

• Kemler R
• Classical cadherins.
• Semin Cell Biol. 1992; 3: 149-55
• Display abstract

• Cadherins represent a gene family of Ca(2+)-dependent cell adhesion molecules (CAMs) identified during development and in adult organs. They generally mediate cell-cell adhesion by homotypic interaction, although heterotypic binding between different cadherin molecules is possible. Molecular cloning and sequence comparison has led to the characterization of a highly homologous group of 'classical' cadherins and more distantly related members, together composing a gene superfamily. The classical cadherins are transmembrane glycoproteins which exhibit, in addition to the structural homologies, a very similar overall protein topology. Protein sequence comparison has led to the identification of domains of common functional importance. The cytoplasmic domains of cadherins associate with peripheral cytoplasmic proteins termed catenin alpha, beta and gamma with molecular weights of 102, 88 and 80 kDa respectively. This complex formation seems to regulate the adhesive function of cadherins, most likely by connecting cadherins with actin microfilaments. Possible implications of catenins for cadherin function are discussed.

• Vestal DJ, Ranscht B
• Glycosyl phosphatidylinositol--anchored T-cadherin mediates calcium-dependent, homophilic cell adhesion.
• J Cell Biol. 1992; 119: 451-61
• Display abstract

• Cadherins are a family of cell adhesion molecules that exhibit calcium-dependent, homophilic binding. Their function depends on both an HisAlaVal sequence in the first extracellular domain, EC1, and the interaction of a conserved cytoplasmic region with intracellular proteins. T-cadherin is an unusual member of the cadherin family that lacks the HisAlaVal motif and is anchored to the membrane through a glycosyl phosphatidylinositol moiety (Ranscht, B., and M. T. Dours-Zimmermann. 1991. Neuron. 7:391-402). To assay the function of T-cadherin in cell adhesion, we have transfected T-cadherin cDNA into CHO cells. Two proteins, mature T-cadherin and the uncleaved T-cadherin precursor, were produced from T-cadherin cDNA. The T-cadherin proteins differed from classical cadherins in several aspects. First, the uncleaved T-cadherin precursor was expressed, together with mature T-cadherin, on the surface of the transfected cells. Second, in the absence of calcium, T-cadherin was more resistant to proteolytic cleavage than other cadherins. Lastly, in contrast to classical cadherins, T-cadherin was not concentrated into cell-cell contacts between transfected cells in monolayer cultures. In cellular aggregation assays, T-cadherin induced calcium-dependent, homophilic adhesion which was abolished by treatment of T-cadherin-transfected cells with phosphatidylinositol-specific phospholipase C. These results demonstrate that T-cadherin is a functional cadherin that differs in several properties from classical cadherins. The function of T-cadherin in homophilic cell recognition implies that the mechanism of T-cadherin-induced adhesion is distinct from that of classical cadherins.

• Geiger B, Ayalon O
• Cadherins.
• Annu Rev Cell Biol. 1992; 8: 307-32

• Takeichi M
• Cadherin cell adhesion receptors as a morphogenetic regulator.
• Science. 1991; 251: 1451-5
• Display abstract

• Cadherins are a family of cell adhesion receptors that are crucial for the mutual association of vertebrate cells. Through their homophilic binding interactions, cadherins play a role in cell-sorting mechanisms, conferring adhesion specificities on cells. The regulated expression of cadherins also controls cell polarity and tissue morphology. Cadherins are thus considered to be important regulators of morphogenesis. Moreover, pathological examinations suggest that the down-regulation of cadherin expression is associated with the invasiveness of tumor cells.

• Takeichi M, Inuzuka H, Shimamura K, Matsunaga M, Nose A
• Cadherin-mediated cell-cell adhesion and neurogenesis.
• Neurosci Res Suppl. 1990; 13: 926-926
• Display abstract

• Cadherins constitute a molecular family which confers adhesive specificities on cells. Their expression is spatio-temporally regulated in embryos and the multiple types of cadherins are expressed in the nervous system. The inhibition of cadherin action with antibodies resulted in the perturbation of the histogenesis of neural tissues. The sites for determining the binding specificities of cadherins reside in their amino terminal 113 amino acid region. Possible roles of cadherins associated with these properties in neurogenesis are discussed.

• Nose A, Tsuji K, Takeichi M
• Localization of specificity determining sites in cadherin cell adhesion molecules.
• Cell. 1990; 61: 147-55
• Display abstract

• Cadherins are a group of homophilic intercellular adhesion molecules; each member of this family exhibits binding specificity. Here, we attempted to map the sites for the specificities of these molecules by analyzing adhesives selectivities of the cells that express chimeric and point-mutated E- and P-cadherin. The results showed that the amino-terminal 113 amino acid region is essential to determine the specificities, and within this region we could identify especially important sites in which amino acid substitutions altered the binding specificity of cadherins. We also found that the epitopes for antibodies capable of blocking cadherin action are located in this amino-terminal region.

• Blaschuk OW, Sullivan R, David S, Pouliot Y
• Identification of a cadherin cell adhesion recognition sequence.
• Dev Biol. 1990; 139: 227-9
• Display abstract

• The molecular mechanisms by which the cadherins interact with one another to promote cell adhesion have not been elucidated. In particular, the amino acid sequences of the cadherin cell adhesion recognition sites have not been determined. Here we demonstrate that synthetic peptides containing the sequence HAV, which is common to all of the cadherins, inhibit two processes (compaction of eight-cell-stage mouse embryos and rat neurite outgrowth on astrocytes) that are known to be mediated by cadherins. The data suggest that the tripeptide HAV is a component of a cadherin cell adhesion recognition sequence.

• Takeichi M
• Cadherins: a molecular family important in selective cell-cell adhesion.
• Annu Rev Biochem. 1990; 59: 237-52

• Nagafuchi A, Takeichi M
• Transmembrane control of cadherin-mediated cell adhesion: a 94 kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin.
• Cell Regul. 1989; 1: 37-44
• Display abstract

• Cadherins are a family of transmembrane glycoproteins which play a key role in Ca(2+)-dependent cell-cell adhesion. Cytoplasmic domains of these molecules are anchored to the cell cytoskeleton and are required for cadherin function. To elucidate how the function of cadherins is controlled through their cytoplasmic domains, we deleted five different regions in the cytoplasmic domain of E-cadherin. After transfecting L cells with cDNA encoding the mutant polypeptides, we assayed aggregating activity of these transfectants; all these mutant proteins were shown to have an extracellular domain with normal Ca(2+)-sensitivity and molecular weight. Two mutant polypeptides with deletions in the carboxy half of the cytoplasmic domain, however, did not promote cell-cell adhesion and had also lost the ability to bind to the cytoskeleton, whereas the mutant molecules with deletions of other regions retained the ability to promote cell adhesion and to anchor to the cytoskeleton. Thus, the cytoplasmic domain contains a subdomain which was involved in the cell adhesion and cytoskeleton-binding functions. When E-cadherin in F9 cells or in L cells transfected with wild-type or functional mutant cadherin polypeptides was solubilized with nonionic detergents and immunoprecipitated, two additional 94 and 102 kDa components were coprecipitated. The 94 kDa component, however, was not detected in the immunoprecipitates from cells expressing the mutant cadherins which had lost the adhesive function. These results suggest that the interaction of the carboxy half of the cytoplasmic domain with the 94 kDa component regulates the cell binding function of the extracellular domain of E-cadherin.

• Miyatani S et al.
• Neural cadherin: role in selective cell-cell adhesion.
• Science. 1989; 245: 631-5
• Display abstract

• Cadherins are a family of Ca2+-dependent intercellular adhesion molecules. Complementary DNAs encoding mouse neural cadherin (N-cadherin) were cloned, and the cell binding specificity of this molecule was examined. Mouse N-cadherin shows 92 percent similarity in amino acid sequence to the chicken homolog, while it shows 49 percent and 43 percent similarity to epithelial cadherin and to placental cadherin of the same species, respectively. In cell binding assays, mouse N-cadherin did not cross-react with other mouse cadherins, but it did cross-react with chicken N-cadherin. The results indicate that each cadherin type confers distinct adhesive specificities on different cells, and also that the specificity of N-cadherin is conserved between mammalian and avian cells.

• Okada TS
• The expression of cell adhesion molecules, cadherins: markers of kidney morphogenesis.
• Pediatr Nephrol. 1988; 2: 115-7
• Display abstract

• Cadherins are protein molecules that promote cell adhesion in the presence of calcium. There are several classes of cadherins. The expression of two of these, namely the N- and E-cadherins, is intrinsically associated with the embryonic development of the kidney and thus their study provides a molecular basis for understanding the epithelial organization of this organ.

• Takeichi M
• [Cellular and molecular basis for tissue construction: role of cadherins in selective cell adhesion]
• Seikagaku. 1987; 59: 1-9

• Ringwald M et al.
• The structure of cell adhesion molecule uvomorulin. Insights into the molecular mechanism of Ca2+-dependent cell adhesion.
• EMBO J. 1987; 6: 3647-53
• Display abstract

• We have determined the amino acid sequence of the Ca2+-dependent cell adhesion molecule uvomorulin as it appears on the cell surface. The extracellular part of the molecule exhibits three internally repeated domains of 112 residues which are most likely generated by gene duplication. Each of the repeated domains contains two highly conserved units which could represent putative Ca2+-binding sites. Secondary structure predictions suggest that the putative Ca2+-binding units are located in external loops at the surface of the protein. The protein sequence exhibits a single membrane-spanning region and a cytoplasmic domain. Sequence comparison reveals extensive homology to the chicken L-CAM. Both uvomorulin and L-CAM are identical in 65% of their entire amino acid sequence suggesting a common origin for both CAMs.

• Nose A, Nagafuchi A, Takeichi M
• Isolation of placental cadherin cDNA: identification of a novel gene family of cell-cell adhesion molecules.
• EMBO J. 1987; 6: 3655-61
• Display abstract

• Ca2+-dependent cell--cell adhesion molecules, termed cadherins, are classified into subclasses with different tissue distributions and distinct cell--cell binding specificities. We report the cloning of cDNA encoding a cadherin present in the placenta which is called P-cadherin. The deduced sequence encodes a polypeptide of 822 amino acids with the characteristic features of integral membrane proteins. A computer search of the amino acid sequence homology of P-cadherin against itself showed that this molecule contains internal repeats in the extracellular domain. Comparison of the primary structure of P-cadherin with that of the epithelial cadherin (E-cadherin) showed that there is 58% homology in their amino acid sequences. These results provide evidence for our hypothesis that cadherins constitute a gene family.

• Shirayoshi Y, Hatta K, Hosoda M, Tsunasawa S, Sakiyama F, Takeichi M
• Cadherin cell adhesion molecules with distinct binding specificities share a common structure.
• EMBO J. 1986; 5: 2485-8
• Display abstract

• Ca2+-dependent cell--cell adhesion molecules, termed cadherins, are divided into subclasses with distinct tissue distributions and distinct cell-binding specificities. To elucidate the biochemical relationship of these subclasses, we compared the pattern of tryptic cleavage and the partial amino acid sequence of mouse liver E-cadherin with those of chicken brain N-cadherin. Although these two cadherins are distinct in their cell-binding and immunological specificities, they showed an identical mol. wt and a similar tryptic cleavage pattern. We isolated tryptic fragments of E- and N-cadherin, and determined the sequences of nine amino acid residues of their amino terminus. The results showed that sequences of amino acids from the amino terminus to the 7th residues are identical in these two cadherins. We thus suggest that cadherins with distinct specificities have a common genic origin.

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