Employment of the Epidermal Growth Factor Receptor in Growth Factor–Independent Signaling Pathways

T HE traditional view of growth factor receptors and hormone receptors in general is that a specific ligand directly recognizes a highly selective binding site on its cognate receptor and, thereby, activates receptor-dependent signaling and biological responses. In the case of the EGF receptor, several structurally related proteins (EGF, transforming growth factor alpha, amphiregulin, betacellulin, epiregulin, heparin-binding EGF) are recognized as direct agonists. Each of these growth factors binds to the ectodomain of the EGF receptor and provokes its activation through a mechanism that involves dimerization, activation of the receptor tyrosine kinase cytosolic domain, and autophosphorylation of the receptor. This process initiates signaling pathways that lead to mitogenesis. Recently it has become apparent that the EGF receptor is also part of signaling networks activated by stimuli that do not directly interact with this receptor. These stimuli include agonists that specifically bind to other membrane receptors, membrane depolarization agents, and environmental stressors. The data not only show EGF-independent tyrosine phosphorylation of the EGF receptor, but also provide experimental evidence that the EGF receptor participates in the signaling events and cellular responses initiated by these various stimuli. Collectively, the results imply that in the absence of direct agonists the EGF receptor is employed in a wide array of biological signaling processes. The purpose of this article is to review and evaluate these nonclassical uses of the EGF receptor.