Rebay Ilaria
Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
Dev Biol. 2002 Nov 1;251(1):1-17. doi: 10.1006/dbio.2002.0806.
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.
受体酪氨酸激酶（RTK）信号网络在调控所有后生动物的细胞分化、增殖和存活过程中发挥着核心作用。RTK 通路的过度或持续激活与哺乳动物的致癌作用相关，这凸显了防止信号失控的重要性。本综述将聚焦于控制 RTK 介导信号的抑制机制，重点关注从以果蝇为模型系统的研究中发现的保守原理。将讨论两种一般的抑制策略。第一种是阈值调节，该策略假定对抗 RTK 信号的一种有效方式是建立并维持高阈值屏障，以防止对适度信号水平产生不适当反应。高于此水平的通路激活会克服抑制性阻断，并改变平衡以允许诱导信息的正向流动。第二层负调控涉及诱导负反馈回路，这些回路限制信号的范围、强度或持续时间，从而防止因克服阈值屏障所需的高水平激活而导致的信号失控。这种自抑制机制在整个网络的关键点（从受体到下游效应器）减弱信号。
