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Journal of Cellular and Molecular... Jun 2020E-cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E-cadherin function plays a... (Review)
Review
E-cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E-cadherin function plays a crucial role in breast cancer metastases, with worse prognosis and shorter overall survival. In this narrative review, we describe the inactivating mechanisms underlying CDH1 gene activity and its possible translation to clinical practice as a prognostic biomarker and as a potential targeted therapy.
Topics: Biomarkers, Tumor; Breast Neoplasms; Cadherins; Female; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Prognosis
PubMed: 32301282
DOI: 10.1111/jcmm.15140 -
International Journal of Molecular... Oct 2020Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and... (Review)
Review
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.
Topics: Animals; Biomarkers, Tumor; Cadherins; Catenins; Cell Adhesion; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Signal Transduction
PubMed: 33076339
DOI: 10.3390/ijms21207624 -
Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension.Nature Cell Biology Sep 2022Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast....
Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.
Topics: Animals; Blastocyst; Cadherins; Embryonic Stem Cells; Endoderm; Germ Layers; Mammals
PubMed: 36100738
DOI: 10.1038/s41556-022-00984-y -
International Journal of Molecular... Jul 2019Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and... (Review)
Review
Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work continues to focus in the switch E-/N-cadherin and its role in the epithelial-mesenchymal transition. Here, we will discuss the structural and functional properties of a subset of cadherins (cadherin 17, cadherin 5 and cadherin 6) that have an RGD motif in the extracellular domains. This RGD motif is critical for the interaction with α2β1 integrin and posterior integrin pathway activation in cancer metastatic cells. However, other signaling pathways seem to be affected by RGD cadherin interactions, as will be discussed. The range of solid tumors with overexpression or "de novo" expression of one or more of these three cadherins is very wide (gastrointestinal, gynaecological and melanoma, among others), underscoring the relevance of these cadherins in cancer metastasis. Finally, we will discuss different evidences that support the therapeutic use of these cadherins by blocking their capacity to work as integrin ligands in order to develop new cures for metastatic patients.
Topics: Antigens, CD; Cadherins; Humans; Neoplasms; Signal Transduction
PubMed: 31324051
DOI: 10.3390/ijms20133373 -
Current Opinion in Cell Biology Oct 2012Classical cadherins are the principle adhesive proteins at cohesive intercellular junctions, and are essential proteins for morphogenesis and tissue homeostasis. Because... (Review)
Review
Classical cadherins are the principle adhesive proteins at cohesive intercellular junctions, and are essential proteins for morphogenesis and tissue homeostasis. Because subtype-dependent differences in cadherin adhesion are at the heart of cadherin functions, several structural and biophysical approaches have been used to elucidate relationships between cadherin structures, biophysical properties of cadherin bonds, and cadherin-dependent cell functions. Some experimental approaches appeared to provide conflicting views of the cadherin binding mechanism. However, recent structural and biophysical data, as well as computer simulations generated new insights into classical cadherin binding that increasingly reconcile diverse experimental findings. This review summarizes these recent findings, and highlights both the consistencies and remaining challenges needed to generate a comprehensive model of cadherin interactions that is consistent with all available experimental data.
Topics: Adhesiveness; Animals; Binding Sites; Cadherins; Cell Adhesion; Computer Simulation; Humans; Models, Molecular; Protein Binding
PubMed: 22770731
DOI: 10.1016/j.ceb.2012.05.014 -
Traffic (Copenhagen, Denmark) Mar 2020By happy chance, the founding of Traffic in 1999 coincided with a clutch of reports that documented the endocytosis and recycling of classical cadherin adhesion... (Review)
Review
By happy chance, the founding of Traffic in 1999 coincided with a clutch of reports that documented the endocytosis and recycling of classical cadherin adhesion receptors. This stimulated a concerted effort to elucidate the molecular regulation of cadherin endocytosis and to identify its functional implications. In particular, endocytosis provided new perspectives to understand how cadherins are modulated during tissue morphogenesis. In this short article, we consider some of what we have learnt about this problem and identify open questions for future research.
Topics: Cadherins; Cell Adhesion; Endocytosis; Morphogenesis
PubMed: 31912628
DOI: 10.1111/tra.12721 -
Protein Expression and Purification May 2022The dynamic regulation of epithelial adherens junctions relies on all components of the E-cadherin-catenin complex. Previously, the complexes have been partially...
The dynamic regulation of epithelial adherens junctions relies on all components of the E-cadherin-catenin complex. Previously, the complexes have been partially reconstituted and composed only of α-catenin, β-catenin, and the E-cadherin cytoplasmic domain. However, p120-catenin and the full-length E-cadherin including the extracellular, transmembrane, and intra-cellular domains are vital to the understanding of the relationship between extracellular adhesion and intracellular signaling. Here, we reconstitute the complete and full-length cadherin-catenin complex, including full-length E-cadherin, α-catenin, β-catenin, and p120-catenin, into nanodiscs. We are able to observe the cadherin in nanodiscs by cryo-EM. We also reconstitute α-catenin, β-catenin, and p120-catenin with the E-cadherin cytoplasmic tail alone in order to analyze the affinities of their binding interactions. We find that p120-catenin does not associate strongly with α- or β-catenin and binds much more transiently to the cadherin cytoplasmic tail than does β-catenin. Overall, this work creates many new possibilities for biochemical studies understanding transmembrane signaling of cadherins and the role of p120-catenin in adhesion activation.
Topics: Cadherins; Catenins; Cell Adhesion; Cell Membrane; Phosphoproteins; Signal Transduction; beta Catenin
PubMed: 35063654
DOI: 10.1016/j.pep.2022.106056 -
Annual Review of Pathology Jan 2022Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal... (Review)
Review
Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmocollins, are related to the classical cadherins, but their cytoplasmic domains are tailored for anchoring intermediate filaments instead of actin to sites of cell-cell adhesion. The resulting junctions are critical for resisting mechanical stress in tissues such as the skin and heart. Desmosomal cadherins also act as signaling hubs that promote differentiation and facilitate morphogenesis, creating more complex and effective tissue barriers in vertebrate tissues. Interference with desmosomal cadherin adhesive and supra-adhesive functions leads to a variety of autoimmune, hereditary, toxin-mediated, and malignant diseases. We review our current understanding of how desmosomal cadherins contribute to human health and disease, highlight gaps in our knowledge about their regulation and function, and introduce promising new directions toward combatting desmosome-related diseases.
Topics: Cadherins; Cell Adhesion; Desmocollins; Desmosomes; Humans; Signal Transduction
PubMed: 34425055
DOI: 10.1146/annurev-pathol-042320-092912 -
Sub-cellular Biochemistry 2012Classical cadherins are a family of transmembrane proteins that mediate cell-cell adhesion at adherens junctions. A complex chain of cis- and trans- interactions between... (Review)
Review
Classical cadherins are a family of transmembrane proteins that mediate cell-cell adhesion at adherens junctions. A complex chain of cis- and trans- interactions between cadherin ectodomains establishes a cadherin adhesive cluster. A principal adhesive interaction in such clusters is an exchange of β strands between the first extracellular cadherin domains (EC1). The structure of cadherin adhesive clusters can be modified by other adherens junction proteins including additional transmembrane proteins, nectins and various intracellular proteins that directly or indirectly interact with the intracellular cadherin region. These interactions determine the dynamics and stability of cadherin adhesive structures.
Topics: Adherens Junctions; Animals; Cadherins; Cell Adhesion; Humans; Models, Molecular; Protein Multimerization
PubMed: 22674069
DOI: 10.1007/978-94-007-4186-7_5 -
Seminars in Cancer Biology Feb 2020Cell-cell adhesion by adherens junctions controls proliferation and cell polarization and is crucial to maintain epithelial architecture and homeostasis. Downregulation... (Review)
Review
Cell-cell adhesion by adherens junctions controls proliferation and cell polarization and is crucial to maintain epithelial architecture and homeostasis. Downregulation of two of the main components of adherens junctions, E-cadherin and p120, is an often recurring hallmark of carcinomas, causing loss of polarity and increased proliferation, survival and invasion of epithelial cells. On the other hand, tumor-promoting effects of both E-cadherin and p120 have been reported, substantiated by sustained, or even elevated expression of these molecules in many cancers. In this review, we will discuss how expression regulation by EMT, E-cadherin cleavage or p120 isoform expression can contribute to either tumor-supressing or tumor-promoting processes. Furthermore, we will focus on the contradictory functions of E-cadherin and p120 in the different phases of tumor progression, from carcinoma in situ up to the formation of distant metastasis. Finally, we will discuss the possibilities and challenges when using either protein as a biomarker.
Topics: Animals; Apoptosis; Biomarkers, Tumor; Cadherins; Catenins; Cell Adhesion; Disease Progression; Disease Susceptibility; Gene Expression Regulation; Humans; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Neoplastic Cells, Circulating; Prognosis; Signal Transduction; Delta Catenin
PubMed: 31369816
DOI: 10.1016/j.semcancer.2019.07.020