title: Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing.
abstract: Keratinocyte proliferation and migration are essential to cutaneous wound healing and are, in part, mediated in an autocrine fashion by epidermal growth factor receptor (EGFR)-ligand interactions. EGFR ligands are initially synthesized as membrane-anchored forms, but can be processed and shed as soluble forms. We provide evidence here that wound stimuli induce keratinocyte shedding of EGFR ligands in vitro, particularly the ligand heparin-binding EGF-like growth factor (HB-EGF). The resulting soluble ligands stimulated transient activation of EGFR. OSU8-1, an inhibitor of EGFR ligand shedding, abrogated the wound-induced activation of EGFR and caused suppression of keratinocyte migration in vitro. Soluble EGFR-immunoglobulin G-Fcgamma fusion protein, which is able to neutralize all EGFR ligands, also suppressed keratinocyte migration in vitro. The application of OSU8-1 to wound sites in mice greatly retarded reepithelialization as the result of a failure in keratinocyte migration, but this effect could be overcome if recombinant soluble HB-EGF was added along with OSU8-1. These findings indicate that the shedding of EGFR ligands represents a critical event in keratinocyte migration, and suggest their possible use as an effective clinical treatment in the early phases of wound healing.
authors.affiliation: Department of Biochemistry, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tokumaru
authors.forename: S
authors.initials: S
authors.lastname: Higashiyama
authors.forename: T
authors.initials: T
authors.lastname: Endo
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: J I
authors.initials: JI
authors.lastname: Miyagawa
authors.forename: K
authors.initials: K
authors.lastname: Yamamori
authors.forename: Y
authors.initials: Y
authors.lastname: Hanakawa
authors.forename: H
authors.initials: H
authors.lastname: Ohmoto
authors.forename: K
authors.initials: K
authors.lastname: Yoshino
authors.forename: Y
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
authors.forename: N
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D011480:Protease Inhibitors / Q000494:pharmacology; D012867:Skin / Q000293:injuries*; D014945:Wound Healing / Q000502:physiology*
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; C415836:OSU8 1; D011480:Protease Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000409:Alanine