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The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
Biochemical Journal ( IF 4.4 ) Pub Date : 2021-09-17 , DOI: 10.1042/bcj20210572
Lung-Yu Liang 1 , Michael Roy 1 , Christopher Horne 2 , Jarrod J Sandow 2 , Minglyanna Surudoi 2 , Laura F Dagley 3 , Samuel N Young 3 , Toby Dite 3 , Jeffrey J Babon 3 , Peter W Janes 4 , Onisha Patel 1 , James M Murphy 3 , Isabelle S Lucet 2
Affiliation  

EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell–cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulation is strongly linked to proliferative diseases. However, unlike active Eph receptors, whose catalytic activities are thought to initiate an intracellular signalling cascade, EphB6 and EphA10 are classified as catalytically dead, raising the question of how non-catalytic functions contribute to Eph receptor signalling homeostasis. In this study, we have characterised the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane (JM) region, pseudokinase and SAM domains. Using small-angle X-ray scattering and cross-linking-mass spectrometry, we observed high flexibility within their intracellular regions in solution and a propensity for interaction between the component domains. We identified tyrosine residues in the JM region of EphB6 as EphB4 substrates, which can bind the SH2 domains of signalling effectors, including Abl, Src and Vav3, consistent with cellular roles in recruiting these proteins for downstream signalling. Furthermore, our finding that EphB6 and EphA10 can bind ATP and ATP-competitive small molecules raises the prospect that these pseudokinase domains could be pharmacologically targeted to counter oncogenic signalling.

中文翻译:

EphB6 和 EphA10 受体酪氨酸假激酶的细胞内结构域作为动态信号中枢

EphB6 和 EphA10 是 Eph 受体家族中两个特征不佳的假激酶成员,它们共同作为接触依赖性细胞间通讯的介质,将细胞外信号传递为细胞内信号。根据它们的活跃对应物,EphB6 和 EphA10 失调与增殖性疾病密切相关。然而,与活性 Eph 受体不同,其催化活性被认为会启动细胞内信号级联反应,EphB6 和 EphA10 被归类为催化死亡,这就提出了非催化功能如何促进 Eph 受体信号稳态的问题。在这项研究中,我们表征了 EphB6 和 EphA10 细胞内区域的生化特性和拓扑结构,包括近膜 (JM) 区域、假激酶和 SAM 结构域。使用小角度 X 射线散射和交联质谱,我们观察到溶液中细胞内区域的高度灵活性和组分域之间相互作用的倾向。我们将 EphB6 的 JM 区域中的酪氨酸残基鉴定为 EphB4 底物,其可以结合信号效应器的 SH2 域,包括 Abl、Src 和 Vav3,这与招募这些蛋白质用于下游信号传导的细胞作用一致。此外,我们发现 EphB6 和 EphA10 可以结合 ATP 和 ATP 竞争性小分子,这提出了这些假激酶结构域可以在药理学上靶向对抗致癌信号的前景。我们将 EphB6 的 JM 区域中的酪氨酸残基鉴定为 EphB4 底物,其可以结合信号效应器的 SH2 域,包括 Abl、Src 和 Vav3,这与招募这些蛋白质用于下游信号传导的细胞作用一致。此外,我们发现 EphB6 和 EphA10 可以结合 ATP 和 ATP 竞争性小分子,这提出了这些假激酶结构域可以在药理学上靶向对抗致癌信号的前景。我们将 EphB6 的 JM 区域中的酪氨酸残基鉴定为 EphB4 底物,其可以结合信号效应器的 SH2 域,包括 Abl、Src 和 Vav3,这与招募这些蛋白质用于下游信号传导的细胞作用一致。此外,我们发现 EphB6 和 EphA10 可以结合 ATP 和 ATP 竞争性小分子,这提出了这些假激酶结构域可以在药理学上靶向对抗致癌信号的前景。
更新日期:2021-09-15
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