Epigen (EPGN) is an epithelial mitogen that belongs to the EGF superfamily (1-3). Human Epigen cDNA encodes a 154aa residue type I transmembrane precursor glycoprotein with a 22 aa signal peptide, an 88 aa extracellular domain, a 21 aa transmembrane domain and a 23 aa cytoplasmic domain (2, 3). The extracellular domain (aa 23-110) contains a pattern of six cysteines typical of EGF family proteins (1-3). Potential splice variants of 133, 112, 103, 94 or 73 aa, lacking either N-terminal sequence (aa 15 or 36 to 44), transmembrane and juxtamembrane sequence (aa 87 or 96 to 137), or sequences in both regions, have been described (4). In addition to potentially secreted splice variants, Epigen is among several EGF family proteins that can undergo metalloproteinase cleavage to generate a soluble form (3, 5). Cleavage of Epigen by TACE/ADAM17 has been demonstrated (5). The mature, shed form of human Epigen (aa 54-104) shares 92%, 94% and 94% aa sequence identity with mouse, rat and equine Epigen, respectively, and more than 40% aa identity with corresponding regions of TGF-a and epiregulin (2). Epigen mRNA is found in many tissues, but it is mainly expressed in actively proliferating cells within these tissues. For example, Epigen in skin is found mainly in the proliferating root sheath of hair follicles, and transgenic overexpression in the skin causes hyperplasia in sebaceous glands (3, 6). Epigen is also expressed developmentally and by invasive adenocarcinomas of the breast and prostate (3). Epigen is strongly mitogenic for epithelial cells and fibroblasts, despite its relatively weak affinity for its main receptor, ErbB1 (2, 3). The mitogenic potential of Epigen is enhanced by its unusually long persistence on the membrane before ubiquitylation and receptor-mediated depletion (3).