15 Folia Medica LI (3) July - Sept 2009 MEMBERS OF THE EGF RECEPTOR FAMILY IN NORMAL AND PATHOLOGICAL EPIDERMIS Yves Poumay, Vanio Mitev 1 Cell and Tissue Laboratory, URPHYM, University of Namur (FUNDP), Belgium, 1 Department of Biochem- istry, Medical University, Sofia, Bulgaria ABSTRACT Epidermal growth factor (EGF) and analogs bind to transmembrane receptors that exhibit tyrosine kinase activity in their cytoplasmic domain and which belong to the EGF receptor family. These growth factors and relevant receptors were named after initial identification of the functions of their founding members in the epidermis. However, since the EGF re- ceptor was recognized as an oncogene, it has been mainly analyzed in cancer; the members of the receptor’s family were also found and characterized initially in tumors and can- cer cells. The present article reviews mainly the expression and function of EGF receptor family members in normal epidermis, together with the expression and function of their respective ligands, and we extend the review to potential involvement of these systems in epidermal disease. Key words: epidermal growth factor, heregulin, c-erbB, neu, skin INTRODUCTION Deregulation of growth factors and protooncogenes expression and activation have been suspected to be potentially critical agents in the pathogenesis of complex skin diseases, including psoriasis and cancer, in which the program of normal epidermal proliferation and differentiation is altered. 1-3 Mul- tiple in vitro and in vivo experiments, including also the production of transgenic mice, have now demonstrated that growth factors and oncogene overexpression in keratinocytes result indeed in variable anomalies in epidermal cell proliferation and differentiation. 4-7 More specifically, a large proportion of the reports addressing the role of growth factors in skin and published during the last fifteen years dealt with the epidermal growth factor (EGF), with its activity-related ligands [transforming growth factor-α (TGF-α), amphiregulin, heparin- binding EGF, epiregulin], and with the so-called EGF receptor, the receptor originally identified by its specific affinity for EGF. 8,9 The number of characterized EGF-related growth factors increased rapidly and the EGF receptor was found to be the first member of a family of growth factor receptors composed of four members (Fig. 1) and named the type 1 family of growth factor receptors. 10 For years, except for the EGF receptor itself, the involvement of the other recep- tors of this family has received very little atten- tion by skin biologists. Most likely, this lack of interest was the result of a longstanding absence of identified ligands showing specificity for those receptors. The identification of such ligands in 1992 led skin biology researchers to pay more attention to other members of the EGF receptor family as receptors involved in skin in general, and in the epidermis in particular. 11,12 Data from our labs, but also from several other labs, have motivated the present short review in which we summarize the knowledge about EGF receptor family members that are of special interest for epidermal biology and pathology. THE EGF RECEPTOR (C-ERBB-1/HER-1) IS AN IMPORTANT EPIDERMAL REGULATOR The EGF receptor, the founding member of the type 1 family of growth factor 10 , is a transmembrane glycoprotein (170 kDa) exhibiting extracellular cysteine-rich regions with high affinity binding capac- ity for EGF, a cytoplasmic domain with characteristic tyrosine kinase activity, and a carboxy-terminal tail with potent autophosphorylation docking sites for signal transduction proteins (phospholipase C-γ, phosphoinositol-3-kinase, Shc or Grb2). Also called c-erbB-1, due to the similarity of its gene with the v-erb gene of avian erythroblastosis virus, the EGF receptor is named in human tissues the Human EGF Receptor-1 (HER1). As a result of EGF binding to Correspondence and reprint request to: Yves Poumay, Cell and Tissue Laboratory, URPHYM, University of Namur (FUNDP), Belgium Received 247 May 2009; Accepted for publication 17 June 2009