PDF(Pubmed)
Abstract：
Signaling proteins in eukaryotes usually comprise a catalytic domain coupled to one or several interaction domains, such as SH2 and SH3 domains. An additional class of proteins critically involved in cellular communication are adapter or scaffold proteins, which fulfill their purely non-enzymatic functions by organizing protein-protein interactions. Intriguingly, certain signaling enzymes, e.g., kinases and phosphatases, have been demonstrated to promote particular cellular functions by means of their interaction domains only. In this review, we will refer to such a function as \"the adapter function of an enzyme\". Though many stories can be told, we will concentrate on several proteins executing critical adapter functions in cells of the immune system, such as Bruton´s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), and SH2-containing inositol phosphatase 1 (SHIP1), as well as in cancer cells, such as proteins of the rat sarcoma/extracellular signal-regulated kinase (RAS/ERK) mitogen-activated protein kinase (MAPK) pathway. We will also discuss how these adaptor functions of enzymes determine or even undermine the efficacy of targeted therapy compounds, such as ATP-competitive kinase inhibitors. Thereby, we are highlighting the need to develop pharmacological approaches, such as proteolysis-targeting chimeras (PROTACs), that eliminate the entire protein, and thus both enzymatic and adapter functions of the signaling protein. We also review how genetic knock-out and knock-in approaches can be leveraged to identify adaptor functions of signaling proteins.
摘要：
真核生物中的信号蛋白通常包含与一个或几个相互作用域偶联的催化域，例如SH2和SH3域。关键参与细胞通讯的另一类蛋白质是衔接蛋白或支架蛋白，通过组织蛋白质-蛋白质相互作用来实现其纯粹的非酶功能。有趣的是，某些信号酶，例如，激酶和磷酸酶，已经被证明仅通过它们的相互作用结构域来促进特定的细胞功能。在这次审查中,我们将这种功能称为“酶的适配器功能”。虽然可以讲很多故事,我们将专注于在免疫系统细胞中执行关键衔接功能的几种蛋白质，例如布鲁顿酪氨酸激酶（BTK），磷脂酰肌醇3-激酶(PI3K),和含SH2的肌醇磷酸酶1（SHIP1），以及在癌细胞中，例如大鼠肉瘤/细胞外信号调节激酶（RAS/ERK）丝裂原活化蛋白激酶（MAPK）途径的蛋白质。我们还将讨论酶的这些衔接子功能如何决定甚至破坏靶向治疗化合物的功效，如ATP竞争性激酶抑制剂。因此，我们强调需要开发药理学方法，如蛋白水解靶向嵌合体(PROTACs)，消除整个蛋白质，以及信号蛋白的酶和衔接子功能。我们还回顾了如何利用遗传敲除和敲入方法来识别信号蛋白的衔接子功能。
