Control of EGF receptor signalling: Lessons from fruitflies

The EGF receptor, and the related ErbB family of receptor tyrosine kinases, have been much implicated in human cancer. Hyperactive receptor signalling promotes deregulated growth control and the onset of malignancy, as well as the disruption of developmental programmes. Very little, however, is known about ErbB physiological regulation in humans. The fruitfly, Drosophila melanogaster, has a single receptor homologous to the four ErbB receptors and in this review we discuss how a genetic approach has led to significant insights into how the fly receptor is regulated. As signalling mechanisms have been well conserved between flies and mammals, these results of experiments in flies are relevant to the study of the human receptors in development and disease. Two areas of recent progress are emphasised. First, a number of signal modulators have been identified, including three EGF receptor inhibitors, several of which have human homologues. Second, we describe how the signalling molecules are integrated into regulatory networks that specify the elaborate activation profiles needed in development - positive and negative feedback control of EGF receptor signalling emerges as a central theme. Although the study of the Drosophila EGF receptor has no direct clinical application, the mechanistic insight it provides suggests new avenues of more applied research, including potential therapeutic targets.