Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways.
Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways.
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DOI：
10.1038/srep32667
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发表时间：
2016-09-07
影响因子：
4.6
通讯作者：
Kiss-Toth E
中科院分区：
文献类型：
--
作者：
Guan H;Shuaib A;Leon DD;Angyal A;Salazar M;Velasco G;Holcombe M;Dower SK;Kiss-Toth E
细胞内信号网络的时空调节是正常细胞生理的关键;其失调导致疾病。三种哺乳动物tribbles蛋白家族通过调节丝裂原活化蛋白激酶（MAPK）、PI 3-激酶诱导的信号传导网络和E3泛素连接酶的活性而成为信号传导的重要控制者。然而，在tribbles的行动中的潜在冗余的重要性，以及如何在各种结合伙伴的亲和力的差异可能会影响信号控制目前还不清楚。我们报告说，tribbles蛋白质可以结合到一个重叠的一组MAPK激酶（MAPKK）在活细胞中，并决定了本地化的复合物。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可能以竞争的方式与MAPKKs相互作用。tribbles对MAPK激活的影响的计算建模表明，该系统对tribbles水平的变化具有很高的敏感性，突出表明这些蛋白质被理想地置于控制并行信号传导途径的激活的动态和平衡。
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.
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DOI：
10.1042/bj20141441
发表时间：
2015-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Bailey FP;Byrne DP;Oruganty K;Eyers CE;Novotny CJ;Shokat KM;Kannan N;Eyers PA
通讯作者：
Eyers PA
影响因子：
3.9
作者：
Kiss-Toth, Endre
通讯作者：
Kiss-Toth, Endre
影响因子：
3.9
作者：
Lohan, Fiona;Keeshan, Karen
通讯作者：
Keeshan, Karen
影响因子：
3.2
作者：
Cunard R
通讯作者：
Cunard R
影响因子：
4.8
作者：
Kiss-Toth, E;Bagstaff, SM;Dower, SK
通讯作者：
Dower, SK