The interplay of double phosphorylation and scaffolding in MAPK pathways.
The interplay of double phosphorylation and scaffolding in MAPK pathways.
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DOI：
10.1016/j.jtbi.2011.11.014
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发表时间：
2012-02-21
影响因子：
2
通讯作者：
Lipniacki, Tomasz
中科院分区：
文献类型：
--
作者：
Kocieniewski, Pawel;Faeder, James R.;Lipniacki, Tomasz
MAPK级联是真核细胞中主要的激酶转导途径。该家族包括RAF/ERK、JNK和p38通路。在MAPK级联反应中，信号通过三层依次激活的激酶（MAP 3 K、MAP 2K和MAPK）传递。后两种激酶需要双重磷酸化才能激活。双重磷酸化要求与级联反应中的双稳态和开关样反应有关。已知MAPK信号传导涉及支架-可以组装蛋白质复合物的多结构域蛋白;在这种情况下，三个MAPK组分。支架被认为通过配对酶和底物来增加信号传导的特异性。支架已经显示出双相控制响应（活化的MAPK的水平）并在一定的支架浓度范围内放大它。为了了解支架和多位点磷酸化的相互作用，在这项研究中，我们分析了简化的MAPK信号转导模型，其中我们假设，无论是单或双磷酸化的MAP 2K和MAPK激活所需的。我们证明了双磷酸化的要求通过支架引导信号传导。在假设的情况下，其中单磷酸化足以激酶活性，支架的存在对响应几乎没有影响。这表明MAPK通路中的双磷酸化虽然不如单磷酸化有效，但与支架一起进化，以确保更严格的控制和更高的信号特异性，通过使支架能够起到响应放大器的作用。
The MAPK cascades are principal kinase transduction pathways in eukaryotic cells. This family includes RAF/ERK, JNK, and p38 pathways. In the MAPK cascade, the signal is transmitted through three layers of sequentially activated kinases, MAP3K, MAP2K, and MAPK. The latter two kinases require dual phosphorylation for activation. The dual phosphorylation requirement has been implicated in bringing about bistability and switch-like responses in the cascade. MAPK signaling has been known to involve scaffolds—multidomain proteins that can assemble protein complexes; in this case the three MAPK components. Scaffolds are thought to increase the specificity of signaling by pairing enzymes and substrates. Scaffolds have been shown to biphasically control the response (the level of activated MAPK) and amplify it at a certain scaffold concentration range. In order to understand the interplay of scaffolding and multisite phosphorylation, in this study we analyze simplified MAPK signaling models in which we assume that either mono- or double phosphorylation of MAP2K and MAPK is required for activation. We demonstrate that the requirement for double phosphorylation directs signaling through scaffolds. In the hypothetical scenario in which mono-phosphorylation suffices for kinase activity, the presence of scaffolds has little effect on the response. This suggests that double phosphorylation in MAPK pathways, although not as efficient as mono-phosphorylation, evolved together with scaffolds to assure the tighter control and higher specificity in signaling, by enabling scaffolds to function as response amplifiers.
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