The Experts below are selected from a list of 1044 Experts worldwide ranked by ideXlab platform
Christoph Redies - One of the best experts on this subject based on the ideXlab platform.
-
Cadherins in Cerebellar Development: Translation of Embryonic Patterning into Mature Functional Compartmentalization
The Cerebellum, 2011Co-Authors: Christoph Redies, Franziska NeudertAbstract:Cadherins are cell adhesion molecules with multiple morphogenic functions in brain development, for example, in neuroblast migration and aggregation, axon navigation, neural circuit formation, and synaptogenesis. More than 100 members of the cadherin superfamily are expressed in the developing and mature brain. Most of the cadherins investigated, in particular classic cadherins and δ-protocadherins, are expressed in the cerebellum. For several cadherin subtypes, expression begins at early embryonic stages and persists until mature stages of cerebellar development. At intermediate stages, distinct Purkinje cell clusters exhibit unique rostrocaudal and mediolateral expression profiles for each cadherin. In the chicken, mouse, and other species, the Purkinje cell clusters are separated by intervening raphes of migrating granule cells. This pattern of Purkinje cell clusters/raphes is, at least in part, continuous with the parasagittal striping pattern that is apparent in the mature cerebellar cortex, for example, for zebrin II/aldolase C. Moreover, subregions of the deep cerebellar nuclei, vestibular nuclei and the olivary complex also express cadherins differentially. Neuroanatomical evidence suggests that the nuclear subregions and cortical domains that express the same cadherin subtype are connected to each other, to form neural subcircuits of the cerebellar system. Cadherins thus provide a molecular code that specifies not only embryonic structures but also functional cerebellar compartmentalization. By following the implementation of this code, it can be revealed how mature functional architecture emerges from embryonic patterning during cerebellar development. Dysfunction of some cadherins is associated with psychiatric diseases and developmental impairments and may also affect cerebellar function.
-
Formation of cadherin-expressing brain nuclei in diencephalic alar plate divisions.
The Journal of comparative neurology, 2000Co-Authors: M S Yoon, Luis Puelles, Christoph RediesAbstract:During the formation of brain nuclei, the vertebrate neural tube is partitioned into distinct embryonic divisions. In this study, the expression of three members of the cadherin family of adhesion molecules (cadherin-6B, cadherin-7, and R-cadherin) was mapped to study the differentiation of gray matter in the division so that diencephalic alar plate of chicken embryos from embryonic day 3 (E3) to E10. At early stages of development (E3-E4), each cadherin is expressed in restricted regions of the diencephalic wall of the neural tube. The borders of some of the expression domains coincide with divisional boundaries. As the mantle layer is formed and increases in thickness from E4 to E8, morphologically discernible aggregates of cells appear that express the three cadherins differentially. These aggregates represent the anlagen of specific diencephalic brain nuclei, e.g., the lateroanterior nucleus, the ventral geniculate nucleus, the nucleus rotundus, the perirotundic area, the principal precommissural nucleus, and the lateral spiriform nucleus. Most of the cadherin-expressing diencephalic nuclei studied in this work apparently derive from a single embryonic division and remain there. The divisional boundaries are replaced gradually by the borders of cadherin-expressing brain nuclei. The current results support the idea that cadherins confer differential adhesiveness to developing structures of gray matter in the diencephalic alar plate. Moreover, they suggest that each cadherin plays a role in the formation of specific brain nuclei within the diencephalic divisions.
-
formation of cadherin expressing brain nuclei in diencephalic alar plate divisions
The Journal of Comparative Neurology, 2000Co-Authors: Minsuk Yoon, Luis Puelles, Christoph RediesAbstract:During the formation of brain nuclei, the vertebrate neural tube is partitioned into distinct embryonic divisions. In this study, the expression of three members of the cadherin family of adhesion molecules (cadherin-6B, cadherin-7, and R-cadherin) was mapped to study the differentiation of gray matter in the divisions of the diencephalic alar plate of chicken embryos from embryonic day 3 (E3) to E10. At early stages of development (E3–E4), each cadherin is expressed in restricted regions of the diencephalic wall of the neural tube. The borders of some of the expression domains coincide with divisional boundaries. As the mantle layer is formed and increases in thickness from E4 to E8, morphologically discernible aggregates of cells appear that express the three cadherins differentially. These aggregates represent the anlagen of specific diencephalic brain nuclei, e.g., the lateroanterior nucleus, the ventral geniculate nucleus, the nucleus rotundus, the perirotundic area, the principal precommissural nucleus, and the lateral spiriform nucleus. Most of the cadherin-expressing diencephalic nuclei studied in this work apparently derive from a single embryonic division and remain there. The divisional boundaries are replaced gradually by the borders of cadherin-expressing brain nuclei. The current results support the idea that cadherins confer differential adhesiveness to developing structures of gray matter in the diencephalic alar plate. Moreover, they suggest that each cadherin plays a role in the formation of specific brain nuclei within the diencephalic divisions. J. Comp. Neurol. 421:461–480, 2000. © 2000 Wiley-Liss, Inc.
-
cadherin defined segments and parasagittal cell ribbons in the developing chicken cerebellum
Molecular and Cellular Neuroscience, 1998Co-Authors: K Arndt, Masatoshi Takeichi, Shinichi Nakagawa, Christoph RediesAbstract:Abstract In the developing chicken cerebellar cortex, three cadherins (Cad6B, Cad7, and R-cadherin) are expressed in distinct parasagittal segments that are separated from each other by ribbons of migrating interneurons and granule cells which express R-cadherin and Cad7, respectively. The segment/ribbon pattern is respected by the expression of other types of molecules, such as engrailed-2 and SC1/BEN/DM-GRASP. The cadherin-defined segments contain young Purkinje cells which are connected to underlying nuclear zones expressing the same cadherin, thereby forming parasagittal cortico-nuclear zones of topographically organized connections. In addition, R-cadherin-positive mossy fiber terminals display a periodic pattern in the internal granular layer. In this layer, Cad7 and R-cadherin are associated with synaptic complexes. These results suggest that cadherins play a pivotal role in the formation of functional cerebellar architecture by providing a three-dimensional scaffold of adhesive information.
-
Cadherin Expression in the Developing Vertebrate CNS: From Neuromeres to Brain Nuclei and Neural Circuits
Experimental Cell Research, 1995Co-Authors: Christoph RediesAbstract:Abstract Cadherins are a family of cell surface glycoproteins which mediate cell-cell adhesion by a Ca2+-dependent mechanism. Results from in vitro studies with cadherin-transfected cell lines show that cadherins preferentially bind to each other in a homophilic fashion. In the developing vertebrate brain, at least 10 cadherins are found. Some of these cadherins are expressed in a restricted fashion in particular developing brain nuclei and neural circuits. Based on these results, specific morphogenetic roles for cadherins during CNS development have been proposed. This review focuses on the possible role of cadherin-mediated sorting and aggregation of early neurons and neurites in the formation of brain nuclei, fiber tracts, and neural circuits. Moreover, at least 1 cadherin is also expressed in a segmental ("neuromeric") fashion in the early chicken forebrain, suggesting that this cadherin regulates developmental processes involved in the transformation from the neuromeric organization of the early neuroepithelium to the functional organization of the mature brain.
Barry Honig - One of the best experts on this subject based on the ideXlab platform.
-
Molecular design principles underlying β-strand swapping in the adhesive dimerization of cadherins
Nature Structural & Molecular Biology, 2011Co-Authors: Jeremie Vendome, Goran Ahlsen, Lawrence Shapiro, Fabiana Bahna, Shoshana Posy, Barry HonigAbstract:The adhesive dimerization interface formed between cadherins involves the swapping of N-terminal β-strands between their EC1 domains. Molecular simulations, combined with biochemical and structural approaches, have unveiled the structural and energetic principles underlying the swapping process. These findings were used to confer strand-swapping properties on a naturally monomeric non-swapping cadherin domain. Cell adhesion by classical cadherins is mediated by dimerization of their EC1 domains through the 'swapping' of N-terminal β-strands. We use molecular simulations, measurements of binding affinities and X-ray crystallography to provide a detailed picture of the structural and energetic factors that control the adhesive dimerization of cadherins. We show that strand swapping in EC1 is driven by conformational strain in cadherin monomers that arises from the anchoring of their short N-terminal strand at one end by the conserved Trp2 and at the other by ligation to Ca^2+ ions. We also demonstrate that a conserved proline-proline motif functions to avoid the formation of an overly tight interface where affinity differences between different cadherins, crucial at the cellular level, are lost. We use these findings to design site-directed mutations that transform a monomeric EC2-EC3 domain cadherin construct into a strand-swapped dimer.
-
structure and binding mechanism of vascular endothelial cadherin a divergent classical cadherin
Journal of Molecular Biology, 2011Co-Authors: Julia Brasch, O J Harrison, Goran Ahlsen, Stewart M Carnally, Robert M Henderson, Barry Honig, Lawrence ShapiroAbstract:Vascular endothelial cadherin (VE-cadherin), a divergent member of the type II classical cadherin family of cell adhesion proteins, mediates homophilic adhesion in the vascular endothelium. Previous investigations with a bacterially produced protein suggested that VE-cadherin forms cell surface trimers that bind between apposed cells to form hexamers. Here we report studies of mammalian-produced VE-cadherin ectodomains suggesting that, like other classical cadherins, VE-cadherin forms adhesive trans dimers between monomers located on opposing cell surfaces. Trimerization of the bacterially produced protein appears to be an artifact that arises from a lack of glycosylation. We also present the 2.1-A-resolution crystal structure of the VE-cadherin EC1-2 adhesive region, which reveals homodimerization via the strand-swap mechanism common to classical cadherins. In common with type II cadherins, strand-swap binding involves two tryptophan anchor residues, but the adhesive interface resembles type I cadherins in that VE-cadherin does not form a large nonswapped hydrophobic surface. Thus, VE-cadherin is an outlier among classical cadherins, with characteristics of both type I and type II subfamilies.
-
sequence and structural determinants of strand swapping in cadherin domains do all cadherins bind through the same adhesive interface
Journal of Molecular Biology, 2008Co-Authors: Lawrence Shapiro, Barry Honig, Shoshana PosyAbstract:Cadherins are cell surface adhesion proteins important for tissue development and integrity. Type I and type II, or “classical”, cadherins form adhesive dimers via an interface formed through the exchange, or “swapping”, of the N-terminal β-strands from their membrane-distal EC1 domains. Here we ask which sequence and structural features in EC1 domains are responsible for β-strand swapping and whether members of other cadherin families also form similar strand-swapped binding interfaces. We first create a comprehensive database consisting of multiple alignments of each type of cadherin domain. We use the known three-dimensional structures of classical cadherins to identify conserved positions in multiple sequence alignments that appear to be crucial determinants of the cadherin domain structure. We further identify features that are unique to EC1 domains. On the basis of our analysis we conclude that all cadherin domains have very similar overall folds but, with the exception of classical and desmosomal cadherin EC1 domains, most of them do not appear to bind through a strand swapping mechanism. Thus, non-classical cadherins that function in adhesion are likely to use different protein-protein interaction interfaces. Our results have implications for the evolution of molecular mechanisms of cadherin-mediated adhesion in vertebrates.
-
Cadherin-mediated cell-cell adhesion: sticking together as a family.
Current Opinion in Structural Biology, 2003Co-Authors: Saurabh D. Patel, Chien Peter Chen, Fabiana Bahna, Barry Honig, L ShapiroAbstract:Abstract The cadherins comprise a family of single-pass transmembrane proteins critical for cell–cell adhesion in vertebrates and invertebrates. The recently determined structure of the whole ectodomain from C-cadherin suggests that the adhesion of cadherins presented by juxtaposed cells is mediated by a strand-swapped dimer in which core hydrophobic elements are exchanged between the partner molecules. Sequence analysis suggests that several cadherin subfamilies share this adhesive mechanism. Recent work has shed new light on the molecular basis of cadherin adhesion, although understanding the specificity of these interactions remains a major challenge.
Margaret J. Wheelock - One of the best experts on this subject based on the ideXlab platform.
-
expression of e cadherin p cadherin and n cadherin in oral squamous cell carcinoma correlation with the clinicopathologic features and patient outcome
Journal of Cranio-maxillofacial Surgery, 2007Co-Authors: Mitsuyoshi Hashimoto, Keith R. Johnson, Margaret J. Wheelock, Je Uk ParkAbstract:Summary Purpose Alteration of cadherin expression is associated with the loss of cellular differentiation, the acquisition of an invasive phenotype and a poor prognosis in many types of cancer. This study aimed to evaluate the immunoreactivity of E-, P- and N-cadherins (cad) in oral squamous cell carcinoma and to correlate their expression with clinicopathological features and clinical outcome. The interaction between the cadherins was also investigated. Methods A total of 71 tissue samples were examined by immunohistochemical methods on paraffin sections using specific antibodies. Results In the primary lesions and lymph node metastases, the immunoreactivity of E-cad was reduced and P-cad was over-expressed, but the expression of N-cad was negative ( p p =0.046 and 0.037, respectively). However, the expression of cadherins did not appear to differ significantly in relation to the histological grade, invasion, tumour size, stage of oral SCC or tumour recurrence. A much greater reduction in the expression of E-cad was found in the positive N-cadherin group ( p =0.008). Nonetheless, cadherin expression was not significantly associated with failure-free survival or overall survival in this experiment subset. Conclusion The reduced E-cad expression and the aberrant N-cad expression are closely associated with each other in oral cancer cases, and this suggests that cadherin switching from E. cad to N. cad may play a critical role in cancer development and metastasis.
-
Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darier’s disease
Journal of Cutaneous Pathology, 2001Co-Authors: Megumi Hakuno, Masashi Akiyama, Margaret J. Wheelock, Hiroshi Shimizu, Takeji NishikawaAbstract:Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darier’s disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases. Method: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299. Results: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases. Conclusions: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.
-
upregulation of p cadherin expression in the lesional skin of pemphigus hailey hailey disease and darier s disease
Journal of Cutaneous Pathology, 2001Co-Authors: Megumi Hakuno, Masashi Akiyama, Margaret J. Wheelock, Hiroshi Shimizu, Takeji NishikawaAbstract:Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darier’s disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases. Method: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299. Results: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases. Conclusions: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.
-
Cadherin and catenin expression in normal human bronchial epithelium and non-small cell lung cancer.
Lung Cancer, 1999Co-Authors: W. Roy Smythe, Keith R. Johnson, Margaret J. Wheelock, Larry R Kaiser, John P. Williams, Steven M AlbeldaAbstract:Abstract Cadherins are transmembrane cell adhesion molecules (CAMS) that mediate cell–cell interactions and are important for maintenance of epithelial cell integrity. This function is dependent on an indirect interaction between the cytoplasmic domain of the cadherin molecule with three cytoplasmic proteins known as α-, β-, and γ-catenin (-cat). Growing evidence suggests that alterations in cadherin or catenin expression or function may be important to the development of an invasive or metastatic phenotype. Immunohistochemical techniques were used to study the expression of the two major epithelial cadherins, E-cadherin (E-cad) and P-cadherin (P-cad) as well as α- and γ-cat in normal bronchial epithelium and in a series of carefully TMN-staged pulmonary adenocarcinomas ( n =21) and squamous cell carcinomas ( n =7). The cadherin profile of normal pseudostratified bronchial epithelium was heterogeneous. Basilar cells strongly expressed P-cad, α- and γ-cat, while columnar cells moderately expressed E-cad, α- and γ-cat. In contrast to other epithelial tumors, E-cad on non-small cell lung carcinomas was actually upregulated, however, a decrease in P-cad expression was noted in 68%. At least one cadherin or catenin was downregulated, compared to normal bronchial epithelium, in 82% of tumors examined. With the exception of an association between loss of P-cad expression and poorly differentiated state, changes in cadherin and catenin expression levels were not significantly correlated to tumor stage, cell type, or nodal status. These findings illustrate that alteration of expression of cadherins and catenins are often found in non-small cell lung carcinoma when compared to the progenitor bronchial epithelium, and may play a role in the development of the malignant phenotype.
-
e cadherin and p cadherin have partially redundant roles in human epidermal stratification
Cell and Tissue Research, 1997Co-Authors: Pamela J Jensen, Brett Telegan, Robert M Lavker, Margaret J. WheelockAbstract:Classical cadherins are Ca2+-dependent homotypic intercellular adhesion molecules that play major regulatory roles in tissue morphogenesis. Human epidermis, which expresses two classical cadherins (E- and P-cadherins), undergoes continual differentiation and morphogenesis, not just during embryonic development, but throughout life. The relative roles of E- and P-cadherin in epidermal morphogenesis have been studied in human epidermal keratinocytes in culture. In these cultures, tissue morphogenesis can be initiated simply by elevation of the extracellular Ca2+ concentration, which activates the cadherins, initiates desmosome organization, and then induces reorganization of the culture from a monolayer into a multilayered, more differentiated, epithelial-like structure. By examination of cultures after several days in high Ca2+, previous data have shown that concurrent inhibition of both E- and P-cadherins nearly abrogates the Ca2+-induced stratification response; however, it has not been possible to discern from these studies whether the two cadherins have unique or redundant regulatory properties. The present study has demonstrated, via electron-microscopic analysis of cultures at an early stage in stratification, that inhibition of either of the cadherins alone does not affect the initiation of stratification, i.e. the formation of up to 2–3 cell layers. Thus, E-cadherin and P-cadherin may have similar regulatory functions with respect to the initiation of stratification. However, if stratification is to continue further to produce a tissue-like structure of 5–7 cell layers, then E-cadherin is required and P-cadherin cannot act as a substitute, presumably because of the distinct localizations of E- and P-cadherins; E-cadherin is found in all cell layers of the stratified epithelium, whereas P-cadherin is lost after the basal keratinocytes become detached from the basement membrane and assume a suprabasal position. Therefore, basal cells, which have two cadherins, can utilize either cadherin to initiate stratification, whereas superficial cells, which have only E-cadherin, are dependent on this cadherin for further stratification.
Lawrence Shapiro - One of the best experts on this subject based on the ideXlab platform.
-
Molecular design principles underlying β-strand swapping in the adhesive dimerization of cadherins
Nature Structural & Molecular Biology, 2011Co-Authors: Jeremie Vendome, Goran Ahlsen, Lawrence Shapiro, Fabiana Bahna, Shoshana Posy, Barry HonigAbstract:The adhesive dimerization interface formed between cadherins involves the swapping of N-terminal β-strands between their EC1 domains. Molecular simulations, combined with biochemical and structural approaches, have unveiled the structural and energetic principles underlying the swapping process. These findings were used to confer strand-swapping properties on a naturally monomeric non-swapping cadherin domain. Cell adhesion by classical cadherins is mediated by dimerization of their EC1 domains through the 'swapping' of N-terminal β-strands. We use molecular simulations, measurements of binding affinities and X-ray crystallography to provide a detailed picture of the structural and energetic factors that control the adhesive dimerization of cadherins. We show that strand swapping in EC1 is driven by conformational strain in cadherin monomers that arises from the anchoring of their short N-terminal strand at one end by the conserved Trp2 and at the other by ligation to Ca^2+ ions. We also demonstrate that a conserved proline-proline motif functions to avoid the formation of an overly tight interface where affinity differences between different cadherins, crucial at the cellular level, are lost. We use these findings to design site-directed mutations that transform a monomeric EC2-EC3 domain cadherin construct into a strand-swapped dimer.
-
structure and binding mechanism of vascular endothelial cadherin a divergent classical cadherin
Journal of Molecular Biology, 2011Co-Authors: Julia Brasch, O J Harrison, Goran Ahlsen, Stewart M Carnally, Robert M Henderson, Barry Honig, Lawrence ShapiroAbstract:Vascular endothelial cadherin (VE-cadherin), a divergent member of the type II classical cadherin family of cell adhesion proteins, mediates homophilic adhesion in the vascular endothelium. Previous investigations with a bacterially produced protein suggested that VE-cadherin forms cell surface trimers that bind between apposed cells to form hexamers. Here we report studies of mammalian-produced VE-cadherin ectodomains suggesting that, like other classical cadherins, VE-cadherin forms adhesive trans dimers between monomers located on opposing cell surfaces. Trimerization of the bacterially produced protein appears to be an artifact that arises from a lack of glycosylation. We also present the 2.1-A-resolution crystal structure of the VE-cadherin EC1-2 adhesive region, which reveals homodimerization via the strand-swap mechanism common to classical cadherins. In common with type II cadherins, strand-swap binding involves two tryptophan anchor residues, but the adhesive interface resembles type I cadherins in that VE-cadherin does not form a large nonswapped hydrophobic surface. Thus, VE-cadherin is an outlier among classical cadherins, with characteristics of both type I and type II subfamilies.
-
sequence and structural determinants of strand swapping in cadherin domains do all cadherins bind through the same adhesive interface
Journal of Molecular Biology, 2008Co-Authors: Lawrence Shapiro, Barry Honig, Shoshana PosyAbstract:Cadherins are cell surface adhesion proteins important for tissue development and integrity. Type I and type II, or “classical”, cadherins form adhesive dimers via an interface formed through the exchange, or “swapping”, of the N-terminal β-strands from their membrane-distal EC1 domains. Here we ask which sequence and structural features in EC1 domains are responsible for β-strand swapping and whether members of other cadherin families also form similar strand-swapped binding interfaces. We first create a comprehensive database consisting of multiple alignments of each type of cadherin domain. We use the known three-dimensional structures of classical cadherins to identify conserved positions in multiple sequence alignments that appear to be crucial determinants of the cadherin domain structure. We further identify features that are unique to EC1 domains. On the basis of our analysis we conclude that all cadherin domains have very similar overall folds but, with the exception of classical and desmosomal cadherin EC1 domains, most of them do not appear to bind through a strand swapping mechanism. Thus, non-classical cadherins that function in adhesion are likely to use different protein-protein interaction interfaces. Our results have implications for the evolution of molecular mechanisms of cadherin-mediated adhesion in vertebrates.
-
c cadherin ectodomain structure and implications for cell adhesion mechanisms
Science, 2002Co-Authors: Titus J Boggon, Barry M Gumbiner, John Murray, Sophie Chappuisflament, Ellen Wong, Lawrence ShapiroAbstract:Cadherins are transmembrane proteins that mediate adhesion between cells in the solid tissues of animals. Here we present the 3.1 angstrom resolution crystal structure of the whole, functional extracellular domain from C-cadherin, a representative “classical” cadherin. The structure suggests a molecular mechanism for adhesion between cells by classical cadherins, and it provides a new framework for understanding both cis (same cell) and trans (juxtaposed cell) cadherin interactions. The trans adhesive interface is a twofold symmetric interaction defined by a conserved tryptophan side chain at the membrane-distal end of a cadherin molecule from one cell, which inserts into a hydrophobic pocket at the membrane-distal end of a cadherin molecule from the opposing cell.
Y Fujita - One of the best experts on this subject based on the ideXlab platform.
-
casein kinase 1 is a novel negative regulator of e cadherin based cell cell contacts
Molecular and Cellular Biology, 2007Co-Authors: Sophie Duprecrochet, Angelica Figueroa, Catherine Hogan, Emma C Ferber, Carl Uli Bialucha, Joanna Adams, Emily C N Richardson, Y FujitaAbstract:Cadherins are the most crucial membrane proteins for the formation of tight and compact cell-cell contacts. Cadherin-based cell-cell adhesions are dynamically established and/or disrupted during various physiological and pathological processes. However, the molecular mechanisms that regulate cell-cell contacts are not fully understood. In this paper, we report a novel functional role of casein kinase 1 (CK1) in the regulation of cell-cell contacts. Firstly, we observed that IC261, a specific inhibitor of CK1, stabilizes cadherin-based cell-cell contacts, whereas the overexpression of CK1 disrupts them. CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846, a highly conserved residue between classical cadherins. Constitutively phosphorylated E-cadherin (S846D) is unable to localize at cell-cell contacts and has decreased adhesive activity. Furthermore, phosphorylated E-cadherin (S846D) has weaker interactions with β-catenin and is internalized more efficiently than wild-type E-cadherin. These data indicate that CK1 is a novel negative regulator of cadherin-based cell-cell contacts.
-
Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts.
Mol Cell Biol, 2007Co-Authors: Y FujitaAbstract:Cadherins are the most crucial membrane proteins for the formation of tight and compact cell-cell contacts. Cadherin-based cell-cell adhesions are dynamically established and/or disrupted during various physiological and pathological processes. However, the molecular mechanisms that regulate cell-cell contacts are not fully understood. In this paper, we report a novel functional role of casein kinase 1 (CK1) in the regulation of cell-cell contacts. Firstly, we observed that IC261, a specific inhibitor of CK1, stabilizes cadherin-based cell-cell contacts, whereas the overexpression of CK1 disrupts them. CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846, a highly conserved residue between classical cadherins. Constitutively phosphorylated E-cadherin (S846D) is unable to localize at cell-cell contacts and has decreased adhesive activity. Furthermore, phosphorylated E-cadherin (S846D) has weaker interactions with beta-catenin and is internalized more efficiently than wild-type E-cadherin. These data indicate that CK1 is a novel negative regulator of cadherin-based cell-cell contacts.
