Regulation of hemidesmosome dynamics and cell signaling by integrin α6β4

ABSTRACT Hemidesmosomes (HDs) are specialized multiprotein complexes that connect the keratin cytoskeleton of epithelial cells to the extracellular matrix (ECM). In the skin, these complexes provide stable adhesion of basal keratinocytes to the underlying basement membrane. Integrin α6β4 is a receptor for laminins and plays a vital role in mediating cell adhesion by initiating the assembly of HDs. In addition, α6β4 has been implicated in signal transduction events that regulate diverse cellular processes, including proliferation and survival. In this Review, we detail the role of α6β4 in HD assembly and beyond, and we discuss the molecular mechanisms that regulate its function.

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Endometrial profilin 1: a key player in embryo-endometrial crosstalk

Clinical and Experimental Reproductive Medicine ◽

10.5653/cerm.2019.03454 ◽

2020 ◽

Vol 47 (2) ◽

pp. 114-121 ◽

Cited By ~ 1

Author(s):

Chang-Jin Lee ◽

Seon-Hwa Hong ◽

Min-Ji Yoon ◽

Kyung-Ah Lee ◽

Jung-Jae Ko ◽

...

Keyword(s):

Cell Adhesion ◽

Epithelial Cells ◽

Molecular Mechanisms ◽

Mouse Embryos ◽

Implantation Failure ◽

Cytoskeletal Networks ◽

Endometrial Epithelial Cells ◽

Embryo Attachment ◽

Cell Cell

Objective: Despite extensive research on implantation failure, little is known about the molecular mechanisms underlying the crosstalk between the embryo and the maternal endometrium, which is critical for successful pregnancy. Profilin 1 (PFN1), which is expressed both in the embryo and in the endometrial epithelium, acts as a potent regulator of actin polymerization and the cytoskeletal network. In this study, we identified the specific role of endometrial PFN1 during embryo implantation.Methods: Morphological alterations depending on the status of PFN1 expression were assessed in PFN1-depleted or control cells grown on Matrigel-coated cover glass. Day-5 mouse embryos were cocultured with Ishikawa cells. Comparisons of the rates of F-actin formation and embryo attachment were performed by measuring the stability of the attached embryo onto PFN1-depleted or control cells.Results: Depletion of PFN1 in endometrial epithelial cells induced a significant reduction in cell-cell adhesion displaying less formation of colonies and a more circular cell shape. Mouse embryos co-cultured with PFN1-depleted cells failed to form actin cytoskeletal networks, whereas more F-actin formation in the direction of surrounding PFN1-intact endometrial epithelial cells was detected. Furthermore, significantly lower embryo attachment stability was observed in PFN1-depleted cells than in control cells. This may have been due to reduced endometrial receptivity caused by impaired actin cytoskeletal networks associated with PFN1 deficiency.Conclusion: These observations definitively demonstrate an important role of PFN1 in mediating cell-cell adhesion during the initial stage of embryo implantation and suggest a potential therapeutic target or novel biomarker for patients suffering from implantation failure.

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The Role of Cell Adhesion and Cytoskeleton Dynamics in the Pathogenesis of the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.649082 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sabeeha Malek ◽

Darius V. Köster

Keyword(s):

Extracellular Matrix ◽

Cell Adhesion ◽

Genetic Basis ◽

Joint Hypermobility ◽

Cytoskeleton Organization ◽

Cellular Processes ◽

Membrane Bound ◽

Spectrum Disorders ◽

Cytoskeleton Dynamics

The Ehlers-Danlos syndromes (EDS) are a group of 13 disorders, clinically defined through features of joint hypermobility, skin hyperextensibility, and tissue fragility. Most subtypes are caused by mutations in genes affecting the structure or processing of the extracellular matrix (ECM) protein collagen. The Hypermobility Spectrum Disorders (HSDs) are clinically indistinguishable disorders, but are considered to lack a genetic basis. The pathogenesis of all these disorders, however, remains poorly understood. Genotype-phenotype correlations are limited, and findings of aberrant collagen fibrils are inconsistent and associate poorly with the subtype and severity of the disorder. The defective ECM, however, also has consequences for cellular processes. EDS/HSD fibroblasts exhibit a dysfunctional phenotype including impairments in cell adhesion and cytoskeleton organization, though the pathological significance of this has remained unclear. Recent advances in our understanding of fibroblast mechanobiology suggest these changes may actually reflect features of a pathomechanism we herein define. This review departs from the traditional view of EDS/HSD, where pathogenesis is mediated by the structurally defective ECM. Instead, we propose EDS/HSD may be a disorder of membrane-bound collagen, and consider how aberrations in cell adhesion and cytoskeleton dynamics could drive the abnormal properties of the connective tissue, and be responsible for the pathogenesis of EDS/HSD.

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Integrin α6β4 recognition of a linear motif of bullous pemphigoid antigen BP230 controls its recruitment to hemidesmosomes

10.1101/402123 ◽

2018 ◽

Cited By ~ 1

Author(s):

José A Manso ◽

Maria Gómez-Hernández ◽

Arturo Carabias ◽

Noelia Alonso-García ◽

Inés García-Rubio ◽

...

Keyword(s):

Crystal Structure ◽

Basement Membrane ◽

Molecular Mechanisms ◽

Mechanical Stability ◽

Human Keratinocytes ◽

Linear Motif ◽

The Third ◽

Linear Sequence ◽

Integrin Α6β4

AbstractMechanical stability of epithelia requires firm attachment to the basement membrane via hemidesmosomes. Dysfunction of hemidesmosomal proteins causes severe skin blistering diseases. Two plakins, plectin and BP230 (BPAG1e), link the integrin α6β4 to intermediate filaments in epidermal hemidesmosomes. Here, we show that a linear sequence within the isoform-specific N-terminal region of BP230 binds to the third and fourth FnIII domains of β4. The crystal structure of the complex and mutagenesis analysis revealed that BP230 binds between the two domains of β4. BP230 induces closing of the two FnIII domains that are looked in place by an inter-domain ionic clasp required for binding. Disruption of the BP230-β4 interface prevents the recruitment of BP230 to hemidesmosomes in human keratinocytes, revealing a key role of the BP230-β4 interaction for hemidesmosome assembly. Phosphomimetic substitutions in β4 and BP230 disrupt binding. Our study provides insights into the molecular mechanisms of hemidesmosome architecture and regulation.

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MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

Current Pharmaceutical Design ◽

10.2174/1381612826666201029095702 ◽

2020 ◽

Vol 26 ◽

Author(s):

Yini Ma ◽

Xiu Cao ◽

Guojuan Shi ◽

Tianlu Shi

Keyword(s):

Digestive System ◽

Target Genes ◽

Malignant Neoplasm ◽

Vital Role ◽

Diagnostic Biomarkers ◽

Cellular Processes ◽

Promising Therapeutic Target ◽

Direct Target ◽

Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

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Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

Journal of Personalized Medicine ◽

10.3390/jpm11060513 ◽

2021 ◽

Vol 11 (6) ◽

pp. 513

Author(s):

Zheng Zhang ◽

Meng Gu ◽

Zhongze Gu ◽

Yan-Ru Lou

Keyword(s):

Molecular Mechanisms ◽

Neurological Diseases ◽

Cellular Processes ◽

Dna And Rna ◽

Chemotherapeutic Response ◽

Non Coding Rna ◽

Response To Chemotherapy ◽

Personalized Oncology ◽

Long Non Coding Rna

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments.

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Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Current Medicinal Chemistry ◽

10.2174/0929867324666170426095015 ◽

2018 ◽

Vol 25 (1) ◽

pp. 5-21 ◽

Cited By ~ 25

Author(s):

Ylenia Cau ◽

Daniela Valensin ◽

Mattia Mori ◽

Sara Draghi ◽

Maurizio Botta

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Physiological Role ◽

Specific Protein ◽

Protein Protein Interactions ◽

Cellular Processes ◽

Protein Partners ◽

High Sequence Homology ◽

Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

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Nutrigenomics and Life Style Facet- A Modulatory Molecular Evidence in Progression of Breast and Colon Cancer with Emerging Importance

Current Molecular Medicine ◽

10.2174/1566524021666210331151323 ◽

2021 ◽

Vol 21 ◽

Author(s):

Suman Kumar Ray ◽

Sukhes Mukherjee

Keyword(s):

Colon Cancer ◽

Molecular Mechanisms ◽

Health Management ◽

Vital Role ◽

Molecular Evidence ◽

Nutritional Interventions ◽

Phenotypic Alteration ◽

The Individual ◽

Supplement Intake

: Legitimate nutrition assumes a significant role in preventing diseases and, in this way, nutritional interventions establish vital strategies in the area of public health. Nutrigenomics centres on the different genes and diet in an individual and how an individual’s genes influence the reaction to bioactive foodstuff. It targets considering the genetic and epigenetic interactions with nutrients to lead to a phenotypic alteration and consequently to metabolism, differentiation, or even apoptosis. Nutrigenomics and lifestyle factors play a vital role in health management and represent an exceptional prospect for the improvement of personalized diets to the individual at risk of developing diseases like cancer. Concerning cancer as a multifactorial genetic ailment, several aspects need to be investigated and analysed. Various perspectives should be researched and examined regarding the development and prognosis of breast and colon cancer. Malignant growth occurrence is anticipated to upsurge in the impending days, and an effective anticipatory strategy is required. The effect of dietary components, basically studied by nutrigenomics, looks at gene expression and molecular mechanisms. It also interrelates bioactive compounds and nutrients because of different 'omics' innovations. Several preclinical investigations demonstrate the pertinent role of nutrigenomics in breast and colon cancer, and change of dietary propensities is conceivably a successful methodology for reducing cancer risk. The connection between the genomic profile of patients with breast or colon cancer and their supplement intake, it is conceivable to imagine an idea of personalized medicine, including nutrition and medicinal services.

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