Review article
Recent advances in the epidermal growth factor receptor/ligand system biology on skin homeostasis and keratinocyte stem cell regulation

https://doi.org/10.1016/j.jdermsci.2013.05.009Get rights and content

Abstract

The epidermal growth factor (EGF) receptor/ligand system stimulates multiple pathways of signal transduction, and is activated by various extracellular stimuli and inter-receptor crosstalk signaling. Aberrant activation of EGF receptor (EGFR) signaling is found in many tumor cells, and humanized neutralizing antibodies and synthetic small compounds against EGFR are in clinical use today. However, these drugs are known to cause a variety of skin toxicities such as inflammatory rash, skin dryness, and hair abnormalities. These side effects demonstrate the multiple EGFR-dependent homeostatic functions in human skin. The epidermis and hair follicles are self-renewing tissues, and keratinocyte stem cells are crucial for maintaining these homeostasis. A variety of molecules associated with the EGF receptor/ligand system are involved in epidermal homeostasis and hair follicle development, and the modulation of EGFR signaling impacts the behavior of keratinocyte stem cells. Understanding the roles of the EGF receptor/ligand system in skin homeostasis is an emerging issue in dermatology to improve the current therapy for skin disorders, and the EGFR inhibitor-associated skin toxicities. Besides, controlling of keratinocyte stem cells by modulating the EGF receptor/ligand system assures advances in regenerative medicine of the skin. We present an overview of the recent progress in the field of the EGF receptor/ligand system on skin homeostasis and regulation of keratinocyte stem cells.

Introduction

The epidermis and hair follicles constantly renew thanks to keratinocyte stem cells located in the basal layer of the epidermis, and in bulge area [1]. Dividing keratinocyte stem cells generate cells with more restricted growth potential that generate, in turn, suprabasal cells that will terminally differentiate to contribute to the barrier function of skin. A variety of growth factors and cytokines participate in skin homeostasis through the regulation of keratinocyte stem cells [2]. Epidermal growth factor (EGF) receptor (EGFR) signaling is essential for epidermal and hair follicle homeostasis, and dysregulation of the EGF receptor/ligand system and aberrant activation of EGFR signaling is involved in non-melanoma skin cancer and chronic inflammatory disorders, such as psoriasis, atopic dermatitis, and allergic contact dermatitis [3], [4], [5]. Excessive activation of EGFR signaling by over expression of, or mutations in, EGFR is also found in various types of human tumors, making EGFR a widely recognized target for cancer therapy [6]. Although humanized neutralizing antibodies and synthetic small compounds against EGFR are in clinical use today [7], these drugs are known to cause a variety of skin toxicities, including acneiform skin rash, skin dryness (xerosis), itching (pruritus), paronychia, nail changes, hair abnormalities, mucositis, and increased growth of the eyelashes (trichomegaly) or facial hair [8]. These side effects derive from the impairment of the multiple EGFR-dependent homeostatic functions of the skin. EGFR signaling is involved in re-epithelialization of epidermal wound healing [3] and proliferation of keratinocyte stem cells in vivo [9]. Furthermore, activation of EGFR signaling is important for the massive ex vivo expansion of human keratinocyte stem cells [10], [11], which has enabled the autologous transplantation of confluent sheets of cultured keratinocytes onto patients with extensive burns and genetic disorders, and the successful application of human stem cells for regenerative medicine [12], [13]. Thus, a more precise comprehension of roles of the EGF receptor/ligand system on keratinocyte stem cells is indispensable to understand epidermal and hair follicle homeostasis. This knowledge would improve the therapy for skin disorders and alleviate the EGFR inhibitor-associated adverse effects. Furthermore, regulation of keratinocyte stem cells by modulating the EGF receptor/ligand system will further advance regenerative medicine of the skin

Section snippets

The EGF receptor/ligand system

Seven members of EGFR-ligands have been identified so far: EGF, transforming growth factor-α (TGF-α), amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EREG), and epigen (EPGN) [14]. All EGFR-ligands are synthesized as their membrane-anchored forms (proEGFR-ligands), and are proteolytically cleaved to become soluble forms. This process, termed ‘ectodomain shedding’, is mainly mediated by a disintegrin and metalloproteases (ADAMs), and required

Roles of the EGF receptor/ligand system on epidermal homeostasis and hair follicle development

There are some excellent articles in which the authors comprehensively review the expression and localization of EGFR and EGFR-ligands in human skin, and the phenotypes of knockout and transgenic mice developed to analyze the in vivo function of the EGF receptor/ligand system in the skin [4], [5], [16]. In this section, we summarize the recent progress in the EGF receptor/ligand system biology on epidermal homeostasis and hair follicle development, and also illustrate the phenotypes of

Roles of the EGF receptor/ligand system on keratinocyte stem cell regulation

Human skin contains keratinocytes that can generate progressively growing colonies that can be serially cultivated for many passages while remaining diploid [27]. Most importantly, cultured keratinocytes can regenerate a functional epidermis when transplanted autologously onto extensively burned patients [12], [13]. These stem cells can undergo at least 180 doublings under appropriated culture conditions, and can generate a progeny large enough to entirely reconstitute the epidermis of an adult

Remnant peptide signaling of proHB-EGF in epidermal keratinocytes

All EGFR-ligands are synthesized as type I transmembrane protein precursors and expressed on the cell surface. Production of soluble EGFR-ligands (amino-terminal fragments) by proEGFR-ligand shedding and subsequent EGFR activation is a main axis on the EGF receptor/ligand signal transduction system. However, ectodomain shedding of membrane-anchored forms of proEGFR-ligands also yields remnant transmembrane peptides, carboxy-terminal fragments (CTF). After proHB-EGF-ligand shedding, remnant

Conclusion and perspectives

The EGF receptor/ligand system stimulates multiple pathways of signal transduction, and is activated by various extracellular stimuli and inter-receptor crosstalk signaling (Fig. 1). This means that the EGF receptor/ligand system gathers information from the microenvironment, integrates them, and controls keratinocyte stem cells. Dissecting of signaling abnormalities associated with the EGF receptor/ligand system in tumors or inflammatory diseases of individual patients allows us to use

Acknowledgements

We thank Drs. K. Hashimoto and Y. Shirakata (Ehime University) for their continuous encouragement and support, and Dr. Alessandro W. Amici (Ecole Polytechnique Fédérale de Lausanne) for critical reading of the manuscript. We apologize that due to limited space many relevant references could not be cited. This work was supported by Postdoctoral Fellowship for Research Abroad from Japan Society for the Promotion of Science (JSPS) to D.N., Grant-in Aid for Scientific Research from JSPS to D.N.

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