Although originally conceived as a basis for malignant cell growth, autocrine signaling networks are currently known to be activated during tissue repair and with in vitro cultivation. In human epidermal keratinocytes, activation of the
epidermal growth factor receptor by cognate
ligands mediates the majority of the autonomous replicative capacity of these cells and is necessary to inhibit differentiation and apoptosis. The importance of
heparin-binding
growth factors in activation of this receptor was first suggested by the strong anti-proliferative effects of soluble
heparin-like molecules on keratinocyte growth. This and related evidence led to the identification of
amphiregulin as a major autocrine factor for keratinocytes. The binding of
amphiregulin and its homolog,
heparin-binding
epidermal growth factor-like
growth factor, to the receptor is potentially amplified by autoinduction and cross-signaling through
epidermal growth factor-related
polypeptides and by transmodulation of other ErbB-family receptors (HER-2, -3, -4) in cells expressing these receptors.
Heparan sulfate proteoglycans and the
tetraspanin family of
membrane-associated proteins appear to act as cofactors in
amphiregulin-driven mitogenesis mediated by the
epidermal growth factor receptor, but
amphiregulin's immunolocalization to keratinocyte nuclei and to filopodia may indicate other potentially novel effects. Following from the observation that
amphiregulin is overexpressed in lesional psoriatic epidermis, the importance of
amphiregulin in hyperproliferative
skin diseases has been further supported by recent studies of the targeted expression of a transgene encoding
keratin 14 promoter-driven human
amphiregulin to the basal epidermis of mice. Founder transgenic mice displayed a morphologic and microscopic cutaneous phenotype that shares characteristics with
psoriasis. Pharmacologic regulation of
amphiregulin's expression and receptor signaling may eventually prove to be an effective strategy in the treatment of hyperproliferative
skin diseases.