Abstract
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 1α (PA-PLA 1α, 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 1α-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 1α was co-localized with TACE, TGFα and tyrosine-phosphorylated EGFR in the IRS. In PA-PLA 1α-deficient hair follicles, cleaved TGFα and tyrosine-phosphorylated EGFR, as well as LPA, were significantly reduced. LPA, P2Y5 agonists and recombinant PA-PLA 1α 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 1αĝ€"LPAĝ€"P2Y5 axis regulates differentiation and maturation of hair follicles via a TACEĝ€"TGFαĝ€"EGFR pathway, thus underscoring the physiological importance of LPA-induced EGFR transactivation.
| Original language | English |
|---|---|
| Pages (from-to) | 4248-4260 |
| Number of pages | 13 |
| Journal | EMBO Journal |
| Volume | 30 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - 2011 Oct 19 |
Keywords
- EGFR transactivation
- hair follicle
- lysophosphatidic acid (LPA)
- transforming growth factor a (TGFa)
- tumour necrosis factor α converting enzyme (TACE)
ASJC Scopus subject areas
- Neuroscience(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)