Soluble form of heparin-binding EGF-like growth factor contributes to retinoic acid-induced epidermal hyperplasia.

Abstract

Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF-family, is thought to be important for keratinocyte functions. HB-EGF is first synthesized as a membrane-anchored form, and its soluble form is released by ectodomain shedding. Here we investigate the role of HB-EGF in epidermal hyperplasia induced by all-trans retinoic acid (tRA) treatment. HB-EGF is normally expressed in epidermis of normal adult mice at very low levels, but topical tRA treatment results in epidermal hyperplasia, concomitant with the strong induction of HB-EGF expression in the suprabasal layer. tRA-induced epidermal hyperplasia was reduced both in the keratinocyte-specific HB-EGF null mice (K5-HB(del/del)) and knock-in mice expressing the uncleavable mutant form of HB-EGF (HB(uc/uc)), as compared with wild-type HB-EGF knock-in mice (HB(lox/lox)). Among ErbB tyrosine kinase receptors, EGF receptor (EGFR) and ErbB2 were selectively activated by tRA treatment in skin from wild-type mice, while the activation of these ErbB receptors was significantly reduced in the skin of HB-EGF null mice. These results indicate that expression of HB-EGF and generation of its soluble form, followed by activation of EGFR and ErbB2, are pivotal processes in tRA-induced epidermal hyperplasia.

• Authors: Rina Kimura, Ryo Iwamoto, Eisuke Mekada
• Journal: Cell structure and function (Cell Struct Funct) Vol. 30 Issue 2 Pg. 35-42 ( 2005) ISSN: 1347-3700 [Electronic] Japan
• PMID: 16357442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hbegf protein, mouse
• Heparin-binding EGF-like Growth Factor
• Intercellular Signaling Peptides and Proteins
• RNA, Messenger
• Tretinoin
• Epidermal Growth Factor
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Animals
• Cell Proliferation (drug effects)
• Epidermal Growth Factor (chemistry, metabolism)
• Epidermis (drug effects, pathology)
• ErbB Receptors (metabolism)
• Female
• Heparin-binding EGF-like Growth Factor
• Hyperplasia (chemically induced, metabolism)
• Immunohistochemistry
• Intercellular Signaling Peptides and Proteins
• Keratinocytes (cytology, metabolism)
• Mice
• Mice, Inbred Strains
• Mice, Transgenic
• RNA, Messenger (metabolism)
• Receptor, ErbB-2 (metabolism)
• Time Factors
• Tretinoin (metabolism, pharmacology)