Regional variation in distribution of EGF receptor in developing and adult

Epidermal growth factor (EGF) is a small polypeptide (6,045 Da molecular mass) originally isolated from the sub-mandibular glands of male mice (Cohen, 1962). EGF stim-ulates both proliferation (Cohen, 1965) and differentiation (Cohen and Elliott, 1963) in epidermis as well as in a vari-ety of epithelial and nonepithelial tissues (Carpenter and Cohen, 1979). Since the discovery of EGF, a family of structurally related growth factors has been identified that includes transforming growth factor, heparin-binding EGF, cripto, heregulin and amphiregulin (Carpenter and Cohen, 1990; Prigent and Lemoine, 1992). This family of growth factors requires a cell surface receptor in order to express their effects. The EGF receptor (EGFR) is a 170 kDa protein that includes an external growth-factor-bind ing domain, a transmembrane domain, and an internal tyro-sine kinase domain. EGFR is a member of a family of receptor tyrosine kinases that includes platelet-derived growth factor receptor, fibroblast growth factor receptor, and insulin-like growth factor receptor (Yarden and Ullrich, 1988). After binding of their specific ligands, the growth factor receptors dimerize and undergo autophosphorylation of specific tyrosine residues. These phosphorylated tyrosine re idues in turn become binding sites for a group of cyto-plasmic signaling proteins that share the Src homology 2 dom in (Pawson and Gish, 1992; Fantl et al., 1992; Kashishian et al, 1992). These signaling proteins, which include phospholipase C, phosphatidylinositol 3-kinase, and the GTPase activating protein Ras, are then capable of acti-vating pathways that instruct the target cell to undergo pro-lifer tion and/or differentiation (Pawson and Gish, 1992). In stratified squamous epithelium, EGFR has been local-ized to the plasma membranes of cells in the basal layer (Green et al., 1983; Gusterson et al., 1984; Nanney et al., 1984). In these studies, which used specific antibodies a d/or 125I-EGF binding assays, EGFR levels diminished rapidly in each subsequent layer superficial to the basal layer, suggesting that EGFR is lost as epithelial cells undergo terminal differentiation. Nonepithelial cells such a