Department of Infection, Immunity &Cardiovascular Disease, University of Sheffield, Beech Hill road, Sheffield, S10 2RX, United Kingdom.
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
Sci Rep. 2016 Sep 7;6:32667. doi: 10.1038/srep32667.
Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways.
细胞内信号网络的时空调节是正常细胞生理的关键;其失调会导致疾病。哺乳动物 tribbles 蛋白家族已成为通过调节丝裂原活化蛋白激酶 (MAPK)、PI3-激酶诱导的信号网络和 E3 泛素连接酶的活性来控制信号的重要控制器。然而,tribbles 作用的潜在冗余性的重要性以及对各种结合伙伴的亲和力差异如何影响信号控制目前尚不清楚。我们报告 tribbles 蛋白可以在活细胞中与一组重叠的 MAPK-kinases (MAPKK) 结合,并决定复合物的定位。转染细胞中的结合研究揭示了共同的调节机制,并表明 tribbles 和 MAPKs 可能以竞争性方式与 MAPKKs 相互作用。对 tribbles 对 MAPK 激活影响的计算模型表明,该系统对 tribbles 水平的变化非常敏感,这突出表明这些蛋白非常适合控制并发信号通路的激活的动力学和平衡。