Soluble Form of Heparin-binding EGF-like Growth Factor Contributes to Retinoic Acid-induced Epidermal Hyperplasia

Abstract

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.

HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans

“…Furthermore, immunoblotting of WT HB-EGF and HB-HB obtained from the all-trans retinoic acid-treated back skin of WT and HB hb/hb mice, respectively, showed comparable protein induction (see Fig. S5G in the supplementary material), similar to that of previously described knock-in mice expressing an uncleavable proHB-EGF mutant (HB uc/uc mice) Kimura et al, 2005). …”

ErbB1 and ErbB4 generate opposing signals regulating mesenchymal cell proliferation during valvulogenesis

“…Only a limited number of studies have investigated these issues. For example, previous studies have demonstrated that HB-EGF contributes to mouse heart muscle homeostasis and trans-retinoic-acid-induced skin hyperplasia (Kimura et al, 2005) through ErbB2-ErbB4 and ErbB1-ErbB2 heterodimers, respectively. HB-EGF and TGFα have been shown to synergistically contribute to skin epithelial sheet migration in mouse eyelid closure (Mine et al, 2005) and alveolar development (Minami et al, 2008) through ErbB1, although the partner of ErbB1 has not been identified.…”

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

“…(21) HB-EGF gene expression has been demonstrated in a variety of tissues, predominantly the lung, heart, brain and skeletal muscle. (22) HB-EGF participates in a variety of physiological and pathological processes, (11) including wound healing, (23) eyelid formation, (24) blastocyst implantation, (25) retinoic acid-induced epidermal hyperplasia (26) and atherosclerosis. (27) Recently, HB-EGF knockout mice have been established.…”