Desmosomal cadherins and signaling: lessons from autoimmune disease.
Autoantibodies from patients suffering from the autoimmune blistering skin disease pemphigus can be applied as tools to study desmosomal adhesion. These autoantibodies targeting the desmosomal cadherins desmoglein (Dsg) 1 and Dsg3 cause disruption of desmosomes and loss of intercellular cohesion. Although pemphigus autoantibodies were initially proposed to sterically hinder desmosomes, many groups have shown that they activate signaling pathways which cause disruption of desmosomes and loss of intercellular cohesion by uncoupling the desmosomal plaque from the intermediate filament cytoskeleton and/or by interfering with desmosome turnover. These studies demonstrate that desmogleins serve as receptor molecules to transmit outside-in signaling and demonstrate that desmosomal cadherins have functions in addition to their adhesive properties. Two central molecules regulating cytoskeletal anchorage and desmosome turnover are p38MAPK and PKC. As cytoskeletal uncoupling in turn enhances Dsg3 depletion from desmosomes, both mechanisms reinforce one another in a vicious cycle that compromise the integrity and number of desmosomes.
Ludwig-Maximilians-Universität (LMU) Munich, Institute of Anatomy and Cell Biology, Department I , Munich , Germany.
Volker
V
Spindler
Jens
J
Waschke
D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology; D051182:Desmogleins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051181:Desmosomal Cadherins / Q000737:chemistry / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism; D006801:Humans; D010392:Pemphigus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001323:Autoantibodies; D051182:Desmogleins; D051181:Desmosomal Cadherins; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases