Regulation and Function of Desmosomal Adhesion

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

We are studying minute structures called desmosomes that act as spot welds between cells, binding them strongly together. These are abundant in tissues such as epidermis and heart muscle that are constantly subjected to physical stress.

Two recent exciting findings from our laboratory form the basis of this project.
1) Strong adhesion by desmosomes can be weakened by a signalling process inside cells involving an enzyme called protein kinase C (PKC). This becomes important when cells need to break free of their adhesions in order to move, for example when epidermal cells need to cover a wound. 2) The sticky molecules responsible for adhesion in desmosomes appear to have an additional function in regulation the thickness and rate of cell division in epidermis.

We will investigate 1) by modifying the proteins of desmosomes in cell so that they cannot receive PKC signals and determine what effect this has on adhesion. In relation to 2) we will determine what genes are affected by desmosomal proteins in epidermis in order to learn what signals are involved in this type of regulation.

The results will further our understanding of how cell adhesion is regulated in normal tissues, in disease and in embryonic development.

Technical Summary

Desmosomes are adhesive intercellular junctions of epithelia and cardiac muscle. They are important in the maintenance of tissue structure, in development and in human disease, including cancer, heart disease, wound healing, autoimmune disease and genetic disease. Our recent research has produced several exciting findings relating to the function and regulation of desmosomes. Two of these findings form the focus of this programme. 1) We have shown that the adhesiveness of desmosomes in cultured epithelial cell sheets and in epidermis is reduced in response to wounding. The reduction in adhesiveness occurs via a signal involving the a isoform of protein kinase C (PKCa). We hypothesise that this adhesive change facilitates down-regulation of adhesion in wound edge cells, permitting them to migrate to re-epithlialise the wound. We believe that the down-regulation may involve internalisation of whole desmosomes by the wound edge cells. These ideas will be tested by site-directed mutagenesis and phosphorylation studies of desmosomal proteins, by analysis of wound healing in normal and PKC-/- mice, and by imaging GFP/YFP-labelled desmosomes and PKCa in wounded cell sheets. 2) Gene deletion and transgenesis with desmosomal cadherins (DCs) in mice, and analysis of human genetic disease suggest that DCs contribute to the regulation of proliferation and differentiation in the epidermis. We will seek evidence for this by microarray analysis of the epidermis of existing knockout and transgenic mice, and by deletion of two DC genes from mice. The results will produce major new insights into the way adhesion is regulates in normal and diseased tissues, and provide evidence for a novel function for desmosomes.

Publications

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Berika M (2014) Desmosomal Adhesion In Vivo in Cell Communication & Adhesion

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Coathup MJ (2017) Controlled laser texturing of titanium results in reliable osteointegration. in Journal of orthopaedic research : official publication of the Orthopaedic Research Society

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Garrod D (2008) Desmosome structure, composition and function. in Biochimica et biophysica acta

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Garrod D (2008) Hyper-adhesion: a new concept in cell-cell adhesion. in Biochemical Society transactions

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Garrod D (2014) Hyper-adhesion: a unique property of desmosomes. in Cell communication & adhesion

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Garrod DR (2008) Pervanadate stabilizes desmosomes. in Cell adhesion & migration

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Goonesinghe A (2012) Desmosomal cadherins in zebrafish epiboly and gastrulation. in BMC developmental biology

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Kimura TE (2007) Calcium-independent desmosomes of keratinocytes are hyper-adhesive. in The Journal of investigative dermatology

 
Description MRC Project Grant
Amount £896,600 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2008 
End 12/2011
 
Description MRC Project Grant
Amount £411,122 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2008 
End 08/2011
 
Description Wellcome Trust Project Grant (Regulation of desmosomal adhesion)
Amount £209,301 (GBP)
Funding ID 086167 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 04/2012
 
Description Desmocollin 1 is abundantly expressed in atherosclerosis and impairs 
Organisation McGill University and Genome Quebec Innovation Centre
Country Canada 
Sector Academic/University 
PI Contribution Supply of Dsc1-/- mouse and general advice on desmosome biology
Collaborator Contribution The biogenesis of high-density lipoprotein (HDL) particles by cholesterol-laden foam cells in atherosclerotic lesions is crucial for the removal of excess cholesterol from the lesions, and impairment in the HDL biogenic process contributes to the progression of atherosclerosis. The aim of this study is to identify novel cellular factors regulating HDL biogenesis. HDL biogenesis is a process of apolipoprotein (apo)-mediated solubilization of specific plasma membrane (PM) microdomains generated in cholesterol accumulated cells. A new method to isolate PM microdomains interacting with the major HDL protein constituent, apoA-I, was established. Lipidomic and proteomic analyses of an isolated PM microdomain revealed that apoA-I binds to cholesterol-rich and desmocollin 1 (DSC1)- containing desmosmes. In this novel apoA-I binding microdomain, DSC1 binds and prevents apoA-I from interacting with another PM microdomain created by ATP-binding cassette transporter A1 (ABCA1) for the formation of HDL. Inhibition of apoA-I-DSC1 binding by silencing DSC1 expression or using DSC1 blocking antibodies makes apoA-I accessible to ABCA1-created microdomains and thus HDL biogenesis. Importantly, DSC1 is abundantly expressed in macrophages and human atherosclerotic lesions, suggesting that DSC1 may contribute to cholesterol accumulation in atherosclerotic lesions by sequestering apoA-I and impairing HDL biogenesis. The binding of apoA-I to two functionally opposing PM microdomains, ABCA1 and DSC1 domains, suggests that HDL biogenesis and PM cholesterol levels may be regulated by the relative abundance of the two domains, and that novel HDL biogenic therapies may be developed by targeting DSC1.
Impact A publication is in revision
Start Year 2014
 
Description Desmocollin 3 expression in mice 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Postdoc carried out mouse work with reporter construct supplied from Birmingham
Impact Paper PubMed ID 16841032
 
Description Down-regulation of desmosomal adhesion 
Organisation Agency for Science, Technology and Research (A*STAR)
Department Institute of Medical Biology
Country Singapore 
Sector Academic/University 
PI Contribution Proposal and joint supervision of graduate student research project.
Collaborator Contribution Joint supervision of project
Impact Reseach is progressing well and should result in publication as well as application for new funding.
Start Year 2014
 
Description EphB2 and EphB3 forward signalling are required for palate development. 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Supervised second half of the project including mouse work, histology and imaging, and writing of paper
Impact Publication PubMed ID 19032981
 
Description EphB2 and EphB3 forward signalling are required for palate development. 
Organisation University of Texas
Country United States 
Sector Academic/University 
PI Contribution Supervised second half of the project including mouse work, histology and imaging, and writing of paper
Impact Publication PubMed ID 19032981
 
Description EphB2 and EphB3 forward signalling are required for palate development. 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution Supervised second half of the project including mouse work, histology and imaging, and writing of paper
Impact Publication PubMed ID 19032981
 
Description Laser surface retexturng of Ti-6Al-4V for improving biocompatibility 
Organisation University of Manchester
Department Faculty of Engineering and Physical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Design and supervision of experiments to study the adhesion of osteoblasts to the surface of laser-treated titanium alloys
Collaborator Contribution It has led to further collaborationFurther collaboration
Impact Further collaborations. Production of a surface that give excellent cell adhesion. Multidisciplinary - Biology and Aerospace
Start Year 2007
 
Description Laser surface retexturng of Ti-6Al-4V for improving biocompatibility 
Organisation University of Manchester
Department Faculty of Engineering and Physical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Design and supervision of experiments to study the adhesion of osteoblasts to the surface of laser-treated titanium alloys
Collaborator Contribution It has led to further collaborationFurther collaboration
Impact Further collaborations. Production of a surface that give excellent cell adhesion. Multidisciplinary - Biology and Aerospace
Start Year 2007
 
Description Nrf2 regulates demosomal adhesion in the epidermis 
Organisation ETH Zurich
Department Molecular Health Sciences Platform
Country Switzerland 
Sector Public 
PI Contribution Advising on research concepts and methodolgy. Provision of reagents.
Collaborator Contribution Initiation of project. Conduct of experimental work.
Impact Publication in Nature Communications. Potential recruitment of research fellow to University of Manchester
Start Year 2012
 
Description The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice. 
Organisation University of Leeds
Department Faculty of Biological Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Supervised cell adhesion work including immunofluorescence, confocal imaging and electron microscopy. Wrote paper
Impact Publication PubMed ID 18703497
 
Description The cell adhesion molecule nectin-1 is critical for normal enamel formation in mice. 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Supervised cell adhesion work including immunofluorescence, confocal imaging and electron microscopy. Wrote paper
Impact Publication PubMed ID 18703497
 
Description School visits 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Lectures to school biology society

Much interest from pupils
Year(s) Of Engagement Activity 2007,2008