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.
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Authors | S Tokumaru, S Higashiyama, T Endo, T Nakagawa, J I Miyagawa, K Yamamori, Y Hanakawa, H Ohmoto, K Yoshino, Y Shirakata, Y Matsuzawa, K Hashimoto, N Taniguchi |
Journal | The Journal of cell biology
(J Cell Biol)
Vol. 151
Issue 2
Pg. 209-20
(Oct 16 2000)
ISSN: 0021-9525 [Print] United States |
PMID | 11038170
(Publication Type: Journal Article)
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Chemical References |
- HBEGF protein, human
- Hbegf protein, mouse
- Heparin-binding EGF-like Growth Factor
- Hydroxamic Acids
- Intercellular Signaling Peptides and Proteins
- Ligands
- Matrix Metalloproteinase Inhibitors
- OSU8 1
- Protease Inhibitors
- Epidermal Growth Factor
- ErbB Receptors
- Alanine
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Topics |
- Alanine
(analogs & derivatives, pharmacology)
- Animals
- Cell Movement
(drug effects)
- Cells, Cultured
- Epidermal Growth Factor
(metabolism)
- ErbB Receptors
(metabolism)
- Female
- Heparin-binding EGF-like Growth Factor
- Humans
- Hydroxamic Acids
(pharmacology)
- Intercellular Signaling Peptides and Proteins
- Keratinocytes
(cytology, physiology)
- Ligands
- Matrix Metalloproteinase Inhibitors
- Mice
- Mice, Inbred BALB C
- Protease Inhibitors
(pharmacology)
- Skin
(injuries)
- Wound Healing
(physiology)
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