title: Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3.
abstract: The cell adhesion molecule plakophilin 3 (Pkp3) plays an essential role in the maintenance of skin integrity and is targeted in certain autoimmune conditions. In one example, we have shown that Pkp3 is instrumental in mediating the discohesive effects of sera from patients with pemphigus vulgaris (PV), a life-threatening autoimmune disease that targets intercellular adhesion in the epidermis. In the present study, we determine the effect of PV autoimmune globulin (PV IgG) on Pkp3 in an in-vitro model of PV. We demonstrate that Pkp3 becomes tyrosine phosphorylated as early as 30 min upon binding of PV IgG to keratinocyte surface and eventually detaches from its binding partner desmoglein 3 (Dsg3). In parallel, Pkp3 is depleted from the membrane (Triton X-soluble) fraction and accumulates in the cytoplasm within 240 min of incubation with PV IgG. Inhibition of Pkp3 phosphorylation by a Src inhibitor attenuates the discohesive effects of PV IgG. Taken together, the data demonstrate that activation of Src-kinase signalling is crucial for PV acantholysis and acts, at least in part, via phosphorylation of the adaptor protein Pkp3.
authors: Melbourne Dental School & Oral Health CRC, The University of Melbourne , Melbourne , Australia .
authors: Nicola
authors: N
authors: Cirillo
authors: Emad
authors: E
authors: AlShwaimi
authors: Michael
authors: M
authors: McCullough
authors: Stephen S
authors: SS
authors: Prime
mesh_terms: D001323:Autoantibodies / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D051184:Desmoglein 3 / Q000235:genetics / Q000276:immunology*; D004817:Epidermis / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010392:Pemphigus / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation; D051191:Plakophilins / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; C071894:DSG3 protein, human; D051184:Desmoglein 3; D007074:Immunoglobulin G; C495339:PKP3 protein, human; D051191:Plakophilins; D047428:Protein Kinase Inhibitors; D014443:Tyrosine; D019061:src-Family Kinases