title: LPA-producing enzyme PA-PLA₁α regulates hair follicle development by modulating EGFR signalling.
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(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.
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. iaska@m.tohoku.ac.jp or
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Naoaki
authors.initials: N
authors.lastname: Arima
authors.forename: Jun
authors.initials: J
authors.lastname: Ishiguro
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D018859:Hair Follicle / Q000201:enzymology / Q000254:growth & development*; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D054466:Phospholipases A1 / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: C082320:LPAR4 protein, human; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D018048:Receptors, Purinergic P2; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C512665:PLA1A protein, human; D054466:Phospholipases A1; C512666:Pla1a protein, mouse; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C032881:lysophosphatidic acid