title: Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A).
abstract: Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a type I transmembrane glycoprotein, is known as one of the most specific lymphatic vessel markers in the skin. In this study, we found that the ectodomain of LYVE-1 undergoes proteolytic cleavage, and this process produces soluble LYVE-1. We further identified the cleavage site for ectodomain shedding and generated an uncleavable mutant of LYVE-1. In lymphatic endothelial cells, ectodomain shedding of LYVE-1 was induced by vascular endothelial growth factor (VEGF)-A, an important factor for angiogenesis and lymphangiogenesis under pathological conditions. VEGF-A-induced LYVE-1 ectodomain shedding was mediated via the extracellular signal-regulated kinase (ERK) and a disintegrin and metalloproteinase (ADAM) 17. Wild-type LYVE-1, but not uncleavable LYVE-1, promoted migration of lymphatic endothelial cells in response to VEGF-A. Immunostaining analyses in human psoriasis skin lesions and VEGF-A transgenic mouse skin suggested that the ectodomain shedding of LYVE-1 occurred in lymphatic vessels undergoing chronic inflammation. These results indicate that the ectodomain shedding of LYVE-1 might be involved in promoting pathological lymphangiogenesis.
authors.affiliation: From the Departments of Dermatology, Biochemistry and Molecular Genetics, and.
authors.forename: Hisayo
authors.initials: H
authors.lastname: Nishida-Fukuda
authors.affiliation: From the Departments of Dermatology.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Araki
authors.affiliation: Bioscience, Advanced Research Support Center (ADRES), Ehime University Graduate School of Medicine, Toon 791-0295, Japan.
authors.forename: Masachika
authors.initials: M
authors.lastname: Shudou
authors.affiliation: From the Departments of Dermatology.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Okazaki
authors.affiliation: Division of Molecular and Cell Biology, Shigei Medical Research Institute, Okayama 701-0202, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tomono
authors.affiliation: Biochemistry and Molecular Genetics, and Strategic Young Researcher Overseas Visiting Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan, Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon 791-0295, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Biochemistry and Molecular Genetics, and Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon 791-0295, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Biochemistry and Molecular Genetics, and Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon 791-0295, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sakaue
authors.affiliation: From the Departments of Dermatology.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.affiliation: From the Departments of Dermatology.
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
authors.affiliation: From the Departments of Dermatology.
authors.forename: Koji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich CH-8093, Switzerland, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.affiliation: Biochemistry and Molecular Genetics, and Strategic Young Researcher Overseas Visiting Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan, Division of Cell Growth and Tumor Regulation, Proteo-Science Center (PROS), Ehime University, Toon 791-0295, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.affiliation: From the Departments of Dermatology, Strategic Young Researcher Overseas Visiting Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan, Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan hirakawa@hama-med.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology; D042601:Lymphatic Vessels / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072198:ADAM17 Protein; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D050505:Mutant Proteins; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C467484:VEGFA protein, human; C492273:LYVE1 protein, mouse; C467480:vascular endothelial growth factor A, mouse
keywords: ADAM; endothelial cell; extracellular signal-regulated kinase (ERK); hyaluronan; lymphangiogenesis; lymphatic endothelial hyaluronan receptor 1 (LYVE-1); psoriasis; shedding; skin; vascular endothelial growth factor (VEGF)