Plakoglobin but not desmoplakin regulates keratinocyte cohesion via modulation of p38MAPK signaling.
Plakoglobin (Pg) and desmoplakin (DP) are adapter proteins within the desmosome, providing a mechanical link between desmosomal cadherins as transmembrane adhesion molecules and the intermediate filament cytoskeleton. As in the severe skin blistering disease pemphigus, autoantibodies against desmosomal adhesion molecules induce loss of keratinocyte cohesion at least in part via p38 mitogen-activated protein kinase (p38MAPK) activation and depletion of desmosomal components, we evaluated the roles of Pg and DP in the p38MAPK-dependent loss of cell adhesion. Silencing of either Pg or DP reduced cohesion of cultured human keratinocytes in dissociation assays. However, Pg but not DP silencing caused activation of p38MAPK-dependent keratin filament collapse and cell dissociation. Interestingly, extranuclear but not nuclear Pg rescued loss of cell adhesion and keratin retraction. In line with this, Pg regulated the levels of the desmosomal adhesion molecule desmoglein 3 and tethered p38MAPK to desmosomal complexes. Our data demonstrate a role of extranuclear Pg in controlling cell adhesion via p38MAPK-dependent regulation of keratin filament organization.
Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany.
Volker
V
Spindler
Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany.
Carina
C
Dehner
Institute of Anatomy and Cell Biology, Julius-Maximilians-Universität, Würzburg, Germany.
Stefan
S
Hübner
Institute of Anatomy and Cell Biology, Department I, Ludwig-Maximilians-Universität, Munich, Germany. Electronic address: jens.waschke@med.uni-muenchen.de.
Jens
J
Waschke
D000818:Animals; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000378:metabolism; D051180:Desmoplakins / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D016086:Lentivirus / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D010392:Pemphigus / Q000276:immunology; D034741:RNA, Small Interfering / Q000378:metabolism; D051185:gamma Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051180:Desmoplakins; D034741:RNA, Small Interfering; D051185:gamma Catenin; D049452:Green Fluorescent Proteins; D007633:Keratins; D048051:p38 Mitogen-Activated Protein Kinases