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LPA‐producing enzyme PA‐PLA 1 α regulates hair follicle development by modulating EGFR signalling
Author(s) -
Inoue Asuka,
Arima Naoaki,
Ishiguro Jun,
Prestwich Glenn D,
Arai Hiroyuki,
Aoki Junken
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.296
Subject(s) - lysophosphatidic acid , biology , transactivation , hair follicle , epidermal growth factor receptor , tyrosine phosphorylation , microbiology and biotechnology , endocrinology , phosphorylation , signal transduction , epidermal growth factor , transforming growth factor , phosphatidic acid , medicine , receptor , biochemistry , transcription factor , phospholipid , membrane , gene
Recent genetic studies of human hair disorders have suggested a critical role of lysophosphatidic acid (LPA) signalling in hair follicle development, mediated by an LPA‐producing enzyme, phosphatidic acid‐selective phospholipase A 1 α (PA‐PLA 1 α, also known as LIPH), and a recently identified LPA receptor, P2Y5 (also known as LPA 6 ). However, the underlying molecular mechanism is unknown. Here, we show that epidermal growth factor receptor (EGFR) signalling underlies LPA‐induced hair follicle development. PA‐PLA 1 α‐deficient mice generated in this study exhibited wavy hairs due to the aberrant formation of the inner root sheath (IRS) in hair follicles, which resembled mutant mice defective in tumour necrosis factor α converting enzyme (TACE), transforming growth factor α (TGFα) and EGFR. PA‐PLA 1 α was co‐localized with TACE, TGFα and tyrosine‐phosphorylated EGFR in the IRS. In PA‐PLA 1 α‐deficient hair follicles, cleaved TGFα and tyrosine‐phosphorylated EGFR, as well as LPA, were significantly reduced. LPA, P2Y5 agonists and recombinant PA‐PLA 1 α enzyme induced P2Y5‐ and TACE‐mediated ectodomain shedding of TGFα through G12/13 pathway and consequent EGFR transactivation in vitro . These data demonstrate that a PA‐PLA 1 α–LPA–P2Y5 axis regulates differentiation and maturation of hair follicles via a TACE–TGFα–EGFR pathway, thus underscoring the physiological importance of LPA‐induced EGFR transactivation.