The 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...
