Ectodomain Shedding of Epidermal Growth Factor Receptor Ligands Is Required for Keratinocyte Migration in Cutaneous Wound Healing

• Published in: The Journal of cell biology 2000-10, Vol.151 (2), p.209-219
• Main Authors: Tokumaru, Sho, Higashiyama, Shigeki, Endo, Takeshi, Nakagawa, Takatoshi, Miyagawa, Jun-ichiro, Yamamori, Katsumi, Hanakawa, Yasushi, Ohmoto, Hiroshi, Yoshino, Kohichiro, Shirakata, Yuji, Matsuzawa, Yuji, Hashimoto, Koji, Taniguchi, Naoyuki
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Alanine - pharmacology; Anatomy & physiology; Animals; Antibodies; Cell growth; Cell lines; Cell Movement - drug effects; Cells; Cells, Cultured; CHO cells; Enzymes; Epidermal Growth Factor - metabolism; ErbB Receptors - metabolism; Female; Heparin-binding EGF-like Growth Factor; Humans; Hydroxamic Acids - pharmacology; Injuries; Intercellular Signaling Peptides and Proteins; Keratinocytes; Keratinocytes - cytology; Keratinocytes - physiology; Ligands; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred BALB C; Neutralizing antibodies; Original; Protease Inhibitors - pharmacology; Skin; Skin - injuries; Tissues; Wound healing; Wound Healing - physiology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.151.2.209

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-Fcγ 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.