Recent studies uncovered critical roles of the adhesion protein E‐cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E‐cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E‐cadherin's functions beyond development, numerous mouse lines with tissue‐specific disruption of Cdh1 have been generated. The consequences of E‐cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete (...) loss of tissue structure and function. This review focuses on these studies and discusses how they provided important insights into E‐cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial‐to‐mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. (shrink)

Cadherins are a large family of single‐pass transmembrane proteins principally involved in Ca2+‐dependent homotypic cell adhesion. The cadherin molecules comprise three domains, the intracellular domain, the transmembrane domain and the extracellular domain, and form large complexes with a vast array of binding partners (including cadherin molecules of the same type in homophilic interactions and cellular protein catenins), orchestrating biologically essential extracellular and intracellular signalling processes. While current, contrasting models for classic cadherin homophilic interaction involve varying numbers of (...) specific repeats found in the extracellular domain, the structure of the domain itself clearly remains the main determinant of cell stability and binding specificity. Through intracellular interactions, cadherin enhances its adhesive properties binding the cytoskeleton via cytoplasmic associated factors α‐ catenin, β‐catenin and p120ctn. Recent structural studies on classic cadherins and these catenin molecules have provided new insight into the essential mechanisms underlying cadherin‐mediated cell interaction and catenin‐mediated cellular signalling. Remarkable structural diversity has been observed in β‐catenin recognition of other cellular factors including APC, Tcf and ICAT, proteins that contribute to or compete with cadherin/catenin functioning. BioEssays 26:497–511, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Diffuse‐type gastric carcinomas show diminished cell‐cell adhesion. A recent paper(1) reports that 50% of these carcinomas contain mutations in the E‐cadherin gene, resulting in the destruction of the calcium‐binding sites of E‐cadherin, and providing strong in vivo evidence that alterations in E‐cadherin play a major role in the development of this particular type of cancer and the short survival of the patients.

Cadherin‐mediated cell‐cell adhesion is perturbed in protein tyrosine kinase (PTK)‐transformed cells. While cadherins themselves appear to be poor PTK substrates, their cytoplasmic binding partners, the Arm catenins, are excellent PTK substrates and therefore good candidates for mediating PTK‐induced changes in cadherin behavior. These proteins, p120ctn, β‐catenin and plakoglobin, bind to the cytoplasmic region of classical cadherins and function to modulate adhesion and/or bridge cadherins to the actin cytoskeleton. In addition, as demonstrated recently for β‐catenin, these proteins also have (...) crucial signaling roles that may or may not be related to their effects on cell‐cell adhesion. Tyrosine phosphorylation of cadherin complexes is well documented and widely believed to modulate cell adhesiveness. The data to date, however, is largely correlative and the mechanism of action remains unresolved. In this review, we discuss the current literature and suggest models whereby tyrosine phosphorylation of Arm catenins contribute to regulation or perturbation of cadherin function. (shrink)

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. (shrink)

The integrity of epithelia depends largely on specialised adhesive structures, the adherens junctions. Several of the components required for building these structures are highly conserved between vertebrates and insects (e.g. E‐cadherin and α‐ and β‐catenin), while others have so far been found only in invertebrates (e.g. crumbs). Two recent papers(1,2) show that the Drosophila E‐cadherin is encoded by the gene shotgun. Phenotypic analyses of shotgun as well as armadillo (β‐catenin) and crumbs mutants provide new insights into the mechanisms (...) by which adherens junctions are built and, further, show that the requirement for E‐cadherin largely depends on the morphogenetic activity of an epithelium. (shrink)

Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin‐containing focal adhesions and cadherin‐containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin‐containing hemidesmosomes oppose force transduction and (...) traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin‐enriched microdomains. This review discusses mechanotransduction by multiple integrin‐ and cadherin‐based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment. (shrink)

New molecular markers for epidermal stem cells have enabled their isolation both in vitro and from the epidermis lying between hair follicles. Micro‐dissection experiments have localised a second population of stem cells within hair follicles. Epidermal stem cells have a patterned distribution in vivo. The patterning can be reconstituted in vitro, showing that it is generated by interactions between keratinocytes and that the differentiation of epidermal stem cells is regulated by signals from other keratinocytes. Recent evidence from transgenic mice suggests (...) that stem cell behaviour in the gut may be regulated by similar cell‐cell interactions in vivo. Candidate genes for mediating these interactions are the homologues of Drosophila cell fate patterning genes such as Notch and Wingless and the Cadherin family of cell‐cell adhesion molecules. The roles of stem cells and of mutations of the Patched gene in epithelial carcinogenesis are discussed. (shrink)

Wnt proteins are involved in a large number of events during development and disease. The crucial element in the transduction of the signal elicited by Wnt is the state and activity of β-catenin. There are two pools of β-catenin, one associated with cadherins at the cell surface and a soluble one in the cytolasm, whose state and concentration are critical for Wnt signalling. In the absence of Wnt, the cytoplasmic pool is low due to targetted degradation of β-catenin. Upon Wnt (...) signalling, β-catenin is stabilized. As a consequence, it can access the nucleus where it interacts with members of the Tcf family of transcription factors to modulate the expression of defined targets. Recent reports indicate that, in addition to Tcfs, β-catenin can interact with other nuclear proteins raising the possibility that Wnt signalling has a wider modulatory effect on transcription than is mediated by its interactions with Tcfs. BioEssays 23:311–318, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The Cry family of Bacillus thuringiensis insecticidal and nematicidal proteins constitutes a valuable source of environmentally benign compounds for the control of insect pests and disease agents. An understanding of Cry toxin resistance at a molecular level will be critical to the long‐term utility of this technology; it may also shed light on basic mechanisms used by other bacterial toxins that target specific organisms or cell types. Selection and cross‐resistance studies have confirmed that genetic adaptation can elicit varying patterns of (...) Cry toxin resistance, which has been associated with deficient protoxin activation by host proteases, and defective Cry toxin‐binding cell surface molecules, such as cadherins, aminopeptidases and glycolipids. Recent work also suggests Cry toxin resistance may be induced in invertebrates as an active immune response. The use of model invertebrates, such as Caenorhabditis elegans and Drosophila melanogaster, as well as advances in insect genomics, are likely to accelerate efforts to clone Cry toxin resistance genes and come to a detailed and broad understanding of Cry toxin resistance. BioEssays 27:614–624, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Tumor progression involves the transition from normal to malignant cells, through a series of cumulative alterations. During this process, invasive and migratory properties are acquired, enabling cells to metastasize (reach and grow in tissues far from their origin). Numerous cellular changes take place during epithelial malignancy, and disruption of E‐cadherin based cell‐cell adhesion is a major event. The small Rho GTPases (Rho, Rac and Cdc42) have been implicated in multiple steps during cellular transformation, including alterations on the adhesion status (...) of the tumor cells. This review focuses on recent in vivo evidence that implicates RhoGTPases in epithelial tumor progression. In addition, we discuss different hypotheses to explain disruption of cadherin‐mediated cell–cell adhesion, directly or indirectly, through activation of Rho GTPases. Understanding the molecular mechanism of how cadherin adhesion and RhoGTPases interplay in normal cells and how this balance is altered during cellular transformation will provide clues as to how to interfere with tumor progression. © 2003 Wiley Periodicals, Inc. BioEssays 25:452–463, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear—while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, (...) we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrβ, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrβ-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM. (shrink)

On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research on apoptosis and differentiation revealed (...) that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an... (shrink)

Experiments carried out on different tumor cell lines showed a significative growth reduction of all treated lines due to the administration of zebrafish embryo extracts withdrawn at different stem cells differentiation stages. Research conducted in order to establish which molecular events were involved in control and downregulation of cancer cell lines demonstrated a transcriptional regulation of the key cell cycle onco-supressor gene, like p53 and a post-translational modification of molecules, like pRb. Research on apoptosis and differentiation processes showed that stem (...) cells differentiating factors induce caspase-3 activation, mainly through E2F-1 gene regulation, thus hyper expressing c-Myc and activating a p73-dependent apoptotic pathway. Moreover, we demonstrated a concurrent and significative normalization of the e-cadherin/β-catenin expression, with an e-cadherin rise. Administration of SCDF in an open clinical randomized clinical trail conducted on 179 patients affected by interme... (shrink)

The mechanisms by which cells become polarised in the plane of an epithelium have been studied in Drosophila for many years. Work has focussed on two key questions: firstly, how individual cells adopt a defined polarity, and secondly how the polarity of each cell within a tissue is aligned with its neighbours. It has been established that asymmetric subcellular localisation of a number of polarity proteins is an essential mechanism underlying polarisation of single cells. The process by which this polarity (...) is coordinated between cells however is less well understood, but is thought to involve gradients of activity of the atypical cadherins Dachsous and Fat. Subsequently, this long‐range polarity signal is refined by local cell–cell interactions involving the transmembrane molecules Frizzled, Strabismus and Flamingo. The role of these factors in coordinating polarity will be discussed. BioEssays 27:1218–1227, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Our understanding of epithelial development in Drosophila has been greatly improved in recent years. Two key regulators of epithelial polarity, Crumbs and DE‐cadherin, have been studied at the genetic and molecular levels and a number of additional genes are being analyzed that contribute to the differentiation of epithelial cell structure. Epithelial architecture has a profound influence on morphogenetic movements, patterning and cell‐type determination. The combination of embryological and genetic/molecular tools in Drosophila will help us to elucidate the complex events (...) that determine epithelial cell structure and how they relate to morphogenesis and other developmental processes. (shrink)

The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF‐SRF to promote (...) activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

New research demonstrates that mechanics can serve as a means of information propagation in developing embryos. Historically, the study of embryonic development has had a dichotomy between morphogens and pattern formation on the one hand and morphogenesis and mechanics on the other. Secreted signals are the preeminent means of information propagation between cells and used to control cell fate, while physical forces act downstream or in parallel to shape tissue morphogenesis. However, recent work has blurred this division of function by (...) demonstrating that mechanics can serve as a means of information propagation. Adhesive or repulsive interactions can propagate through a tissue as a wave. These waves are rapid and directional and can be used to control the flux of cells through a developmental trajectory. Here, two examples are reviewed in which mechanics both guides and mediates morphogenesis and two examples in which mechanics intertwines with morphogens to regulate cell fate. (shrink)