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Neural nitric oxide synthase participates in pemphigus vulgaris acantholysis through upregulation of Rous sarcoma, mammalian target of rapamycin and focal adhesion kinase
Author(s) -
España Agustín,
Mòdol Teresa,
Gil Maria P.,
LópezZabalza Maria J.
Publication year - 2013
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12088
Subject(s) - acantholysis , downregulation and upregulation , focal adhesion , pi3k/akt/mtor pathway , microbiology and biotechnology , proto oncogene tyrosine protein kinase src , pemphigus vulgaris , cancer research , nitric oxide , kinase , chemistry , biology , signal transduction , immunology , biochemistry , autoantibody , endocrinology , antibody , gene
Pemphigus vulgaris ( PV ) is an autoimmune blistering skin disease characterized by suprabasal acantholysis produced as a consequence of desmoglein ( D sg) and non‐ D sg autoantibodies binding to several targeting molecules localized on the membrane of keratinocytes. Nitric oxide ( NO ) may exert a pathogenic function in several immunological processes. We have previously demonstrated that neural nitric oxide synthase ( nNOS ) plays part in PV acantholysis. Also, our group has described a relevant role for HER [human epidermal growth factor receptor ( EGFR ) related] isoforms and several kinases such as Src (Rous sarcoma), mammalian target of rapamycin ( mTOR ) and focal adhesion kinase ( FAK ), as well as caspases in PV development. Using a passive transfer mouse model of PV , we aimed to investigate the relationship between the increase in nNOS and EGFR , Src, mTOR and FAK kinase upregulation observed in PV lesions. Our results revealed a new function for nNOS , which contributes to EGFR ‐mediated PV acantholysis through the upregulation of Src, mTOR and FAK . In addition, we found that nNOS participates actively in PV at least in part by increasing caspase‐9 and caspase‐3 activities. These findings underline the important issue that in PV acantholysis, caspase activation is a nNOS ‐linked process downstream of Src, mTOR and FAK kinase upregulation.