信号传导中配体偏向性的机制与表现：聚焦受体酪氨酸激酶

摘要(中文译文)

生物体的发育和组织稳态的维持依赖于调控基本细胞功能的复杂细胞间信号网络。由于细胞通常同时暴露于多种不同的配体，细胞进化出了不同的细胞内信号传导机制，使细胞能够精确感知并响应其环境。本文讨论配体偏向性（ligand bias）的概念，即不同配体优先激活特定信号通路、从而通过同一受体产生不同响应的能力。尽管偏向性的识别和定量具有挑战性，但已建立的实验方案可用于：(i) 确定是否存在偏好性；(ii) 对这些偏好性进行定量。我们综述了这些方案及其在RTK（单次跨膜受体中最大的家族）信号传导研究中的应用。我们总结了提示RTK存在偏向性信号传导的文献，并讨论了信号偏向性在治疗设计中的实用性。我们讨论了其与GPCR偏向性信号的相似之处，以及多年GPCR信号研究后所获得的经验教训。最后，我们提出RTK配体偏向性在进化中出现，是为了使指导哺乳动物体内组织和器官发育的形态原信号通路多样化。

Abstract

The development of organisms and the maintenance of tissue homeostasis depend on complex intercellular signaling networks that govern basic cell functions. Because cells are typically exposed to many diverse ligands simultaneously, distinct intracellular mechanisms of cell signaling have evolved, allowing cells to accurately sense and respond to their environment. Here, we discuss the concept of ligand bias, which describes the ability of different ligands to preferentially activate specific signaling pathways, and thus produce divergent responses through the same receptor. Although bias can be challenging to identify and quantify, protocols have been established to (i) determine whether preferences exist and (ii) quantify these preferences. We review these protocols and their utility in studies of signaling by RTKs, the largest family of single-pass membrane receptors. We summarize the literature suggesting that RTKs engage in biased signaling and discuss the utility of signaling bias in therapeutics design. We discuss parallels with GPCR biased signaling, and lessons that have been learned after years of GPCR signaling research. Finally, we propose that RTK ligand bias appeared in evolution to diversify the morphogen signaling pathways that direct the development of tissues and organs in the mammalian body.

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