Keeping the receptor tyrosine kinase signaling pathway in check: lessons from Drosophila.

The receptor tyrosine kinase (RTK) signaling network plays a central role in regulating cellular differentiation, proliferation, and survival in all metazoan animals. Excessive or continuous activation of the RTK pathway has been linked to carcinogenesis in mammals, underscoring the importance of preventing uncontrolled signaling. This review will focus on the inhibitory mechanisms that keep RTK-mediated signals in check, with emphasis on conserved principles discerned from studies using Drosophila as a model system. Two general strategies of inhibition will be discussed. The first, threshold regulation, postulates that an effective way of antagonizing RTK signaling is to erect and maintain high threshold barriers that prevent inappropriate responses to moderate signaling levels. Activation of the pathway above this level overcomes the inhibitory blocks and shifts the balance to allow a positive flow of inductive information. A second layer of negative regulation involving induction of negative feedback loops that limit the extent, strength, or duration of the signal prevents runaway signaling in response to the high levels of activation required to surmount the threshold barriers. Such autoinhibitory mechanisms attenuate signaling at critical points throughout the network, from the receptor to the downstream effectors.