Desmosomal interactome in keratinocytes: a systems biology approach leading to an understanding of the pathogenesis of skin disease

We provide the first description of the desmosome network in keratinocytes using a systems level approach. The desmo-adhesome consists of 59 proteins connected by 128 direct interactions and forms different functional subnets. Whilst the structure appears to be extremely robust against random pertur...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2009-11, Vol.66 (21), p.3517-3533
Main Authors: Cirillo, Nicola, Prime, Stephen S.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Adaptor Proteins, Signal Transducing - physiology
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Adhesion - physiology
Cell Biology
Cells, Cultured
Cellular biology
Cytoskeletal Proteins - metabolism
Cytoskeletal Proteins - physiology
Dermatology
Desmosomes - chemistry
Desmosomes - metabolism
Gene expression
Humans
Keratinocytes - metabolism
Life Sciences
Membrane Proteins - metabolism
Metabolic Networks and Pathways - physiology
Metabolome - physiology
Models, Biological
Molecular biology
Pemphigus
Protein Binding
Proteins
Research Article
Skin diseases
Skin Diseases - etiology
Skin Diseases - metabolism
Systems Biology - methods
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Summary:We provide the first description of the desmosome network in keratinocytes using a systems level approach. The desmo-adhesome consists of 59 proteins connected by 128 direct interactions and forms different functional subnets. Whilst the structure appears to be extremely robust against random perturbations, network fragmentation analysis suggests that the desmo-adhesome is susceptible to targeted attacks. To confirm this prediction, we applied this model to the autoimmune disease Pemphigus Vulgaris (PV), a paradigm of external perturbation of the desmosome. Our analysis showed that the adaptor protein plakophilin (Pkp) 3 was in the highest percentile group for both connectivity rate and gene expression changes in experimental PV. This observation led us to speculate that Pkp3 was crucial in desmosomal remodelling, and therefore we designed the experiments to verify this hypothesis. Our data demonstrate that, whilst Pkp3 is important in conferring adhesive strength to keratinocytes, it also acts as a central molecule mediating cell–cell detachment induced by PV IgG.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-009-0139-7