Sarma2012 - Interaction topologies of MAPK cascade (M1_K2_PSEQ_short_duration_signal)

Sarma2012 - Interaction topologies of MAPK cascade (M1_K2_PSEQ_short_duration_signal)

The paper presents the various interaction topologies between the kinases and phosphatases of MAPK cascade. They are represented as M1, M2, M3 and M4. The kinases of the cascades are MKKK, MKK and MK, and Phos1, Phos2 and Phos3 are phosphatases of the system. All three kinases in a M1 type network have specific phosphatases Phos1, Phos2 and Phos3 for the dephosphorylation process. In a M2 type system, kinases MKKK and MKK are dephosphorylated by Phos1 and MK is dephosphorylated by Phos2. The architecture of system like M3 is such that MKKK gets dephosphorylated by Phos1, whereas Phos2 dephosphorylates both MKK and MK. Finally, the MAPK cascade exhibiting more complex design of interaction such as M4 is such that MKKK and MKK are dephosphorylated by Phos1 whereas MKK and MK are dephosphorylated by Phos2. In addition, as it is plausible that the kinases can sequester their respective phosphatases by binding to them, this is considered in the design of the systems (PSEQ-sequestrated system; USEQ-Unsequestrated system). The robustness of different interaction designs of the systems is checked, considering both MichaelisMenten type kinetics (K1) and elementary mass action kinetics (K2). In the living systems, the MAPK cascade transmit both short and long duration signals where short duration signals trigger proliferation and long duration signals trigger cell differentiation. These signal variants are considered to interpret the systems behaviour. It is also tested how the robustness and signal response behaviour of K2 models are affected when K2 assumes quasi steady state (QSS). The combinations of the above variants resulted in 40 models (MODEL1204280001-40). All these 40 models are available from BioModels Database
.
Models that correspond to type M4 with mass-action kinetics K2, in four condition 1) USEQ [ MODEL1204280020
- M4_K2_USEQ], 2) PSEQ [ MODEL1204280024
- M4_K2_PSEQ], 3) QSS_USEQ [ MODEL1204280036
- M4_K2_QSS_USEQ] and 4) QSS_PSEQ [ MODEL1204280040
- M4_K2_QSS_PSEQ] are available from the curated branch. The remaining 36 models can be accessed from the non-curated branch.
This model [ MODEL1204280029
- M1_K2_PSEQ_short_duration_signal] correspond to type M1 with mass action kinetics K2, in short_duration_signal and PSEQ (sequestrated ) condition. This model can accessed from the non-curated branch of BioModels Database
.

This model is described in the article:

Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade.

Sarma U, Ghosh I.
BMC Syst Biol. 2012 Jul 2;6(1):82.
Abstract:

ABSTRACT:

BACKGROUND: The three layer mitogen activated protein kinase (MAPK) signaling cascade exhibits different designs of interactions between its kinases and phosphatases. While the sequential interactions between the three kinases of the cascade are tightly preserved, the phosphatases of the cascade, such as MKP3 and PP2A, exhibit relatively diverse interactions with their substrate kinases. Additionally, the kinases of the MAPK cascade can also sequester their phosphatases. Thus, each topologically distinct interaction design of kinases and phosphatases could exhibit unique signal processing characteristics, and the presence of phosphatase sequestration may lead to further fine tuning of the propagated signal.
RESULTS:

We have built four models of the MAPK cascade, each model with identical kinase-kinase interactions but unique kinases-phosphatases interactions. Our simulations unravelled that MAPK cascade's robustness to external perturbations is a function of nature of interaction between its kinases and phosphatases. The cascade's output robustness was enhanced when phosphatases were sequestrated by their target kinases. We uncovered a novel implicit/hidden negative feedback loop from the phosphatase MKP3 to its upstream kinase Raf-1, in a cascade resembling the B cell MAPK cascade. Notably, strength of the feedback loop was reciprocal to the strength of phosphatases' sequestration and stronger sequestration abolished the feedback loop completely. An experimental method to verify the presence of the feedback loop is also proposed. We further showed, when the models were activated by transient signal, memory (total time taken by the cascade output to reach its unstimulated level after removal of signal) of a cascade was determined by the specific designs of interaction among its kinases and phosphatases.
CONCLUSIONS:

Differences in interaction designs among the kinases and phosphatases can differentially shape the robustness and signal response behaviour of the MAPK cascade and phosphatase sequestration dramatically enhances the robustness to perturbations in each of the cascade. An implicit negative feedback loop was uncovered from our analysis and we found that strength of the negative feedback loop is reciprocally related to the strength of phosphatase sequestration. Duration of output phosphorylation in response to a transient signal was also found to be determined by the individual cascade's kinase-phosphatase interaction design.

This model is hosted on BioModels Database
and identified by: MODEL1204280029
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID: 20587024
.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to [CC0 Public Domain Dedication>http://creativecommons.org/publicdomain/zero/1.0/] for more information.

Sarma2012 - 丝裂原活化蛋白激酶（MAPK）级联的相互作用拓扑结构（M1_K2_PSEQ_short_duration_signal）

该论文阐述了MAPK级联中激酶与磷酸酶的各类相互作用拓扑结构，分别以M1、M2、M3和M4进行标识。该级联中的激酶为MKKK（MAPK激酶激酶激酶，MAPK kinase kinase）、MKK（MAPK激酶激酶，MAPK kinase）与MK（MAPK激酶，MAPK），而Phos1、Phos2和Phos3为本系统中的磷酸酶。在M1型网络中，三种激酶各自对应特异性磷酸酶Phos1、Phos2和Phos3以完成去磷酸化过程。在M2型系统中，激酶MKKK和MKK由Phos1介导去磷酸化，MK则由Phos2介导去磷酸化。M3型系统的架构为：MKKK由Phos1去磷酸化，而Phos2可同时对MKK和MK进行去磷酸化。最后，具有更为复杂相互作用设计的M4型MAPK级联，其MKKK和MKK由Phos1去磷酸化，而MKK和MK由Phos2去磷酸化。此外，考虑到激酶可通过结合磷酸酶对其进行隔离，本系统设计中纳入了该情形（PSEQ为隔离系统；USEQ为非隔离系统）。研究针对米氏动力学（Michaelis-Menten kinetics, K1）与基元质量作用动力学（elementary mass action kinetics, K2）两种情况，检验了不同相互作用设计系统的鲁棒性。在生命系统中，MAPK级联可传递短时程与长时程信号：短时程信号触发细胞增殖，长时程信号触发细胞分化。本研究纳入这两类信号变体以解析系统的行为特性。同时，研究还测试了当K2模型采用准稳态（quasi steady state, QSS）假设时，其鲁棒性与信号响应行为会受到何种影响。上述变体的组合共生成40个模型（MODEL1204280001-40），所有40个模型均可从BioModels数据库获取。

符合M4型、质量作用动力学K2的模型共4个，分别为：1）非隔离状态（USEQ）：MODEL1204280020 - M4_K2_USEQ；2）隔离状态（PSEQ）：MODEL1204280024 - M4_K2_PSEQ；3）准稳态-非隔离状态（QSS_USEQ）：MODEL1204280036 - M4_K2_QSS_USEQ；4）准稳态-隔离状态（QSS_PSEQ）：MODEL1204280040 - M4_K2_QSS_PSEQ，这些模型可从经审核整理分支获取。剩余36个模型可从非经审核整理分支获取。

本模型[MODEL1204280029 - M1_K2_PSEQ_short_duration_signal]对应M1型、质量作用动力学K2、短时程信号及隔离（PSEQ）状态。该模型可从BioModels数据库的非经审核整理分支获取。

本模型对应的发表文章为：《不同激酶-磷酸酶相互作用设计与磷酸酶隔离对MAPK级联鲁棒性及信号流的调控作用》（Different designs of kinase-phosphatase interactions and phosphatase sequestration shapes the robustness and signal flow in the MAPK cascade）
作者为Sarma U, Ghosh I，发表于BMC Syst Biol. 2012 Jul 2;6(1):82。

摘要：
背景：三层丝裂原活化蛋白激酶（MAPK）信号级联的激酶与磷酸酶之间存在多种相互作用设计。尽管级联中三种激酶的序列相互作用高度保守，但该级联的磷酸酶（如MKP3与PP2A）与其底物激酶之间的相互作用却相对多样。此外，MAPK级联的激酶还可隔离其对应的磷酸酶。因此，激酶与磷酸酶的每种拓扑独特的相互作用设计，都可能表现出独特的信号处理特性，而磷酸酶隔离的存在可进一步对传递的信号进行精细调控。
结果：
我们构建了四种MAPK级联模型，每个模型的激酶-激酶相互作用均一致，但激酶-磷酸酶相互作用各不相同。模拟结果显示，MAPK级联对外界扰动的鲁棒性，是其激酶与磷酸酶之间相互作用性质的函数。当磷酸酶被其靶激酶隔离时，级联的输出鲁棒性会得到增强。我们在类似B细胞MAPK级联的模型中，发现了一条从磷酸酶MKP3到其上游激酶Raf-1的新型隐性/隐藏负反馈环路。值得注意的是，该反馈环路的强度与磷酸酶隔离的强度呈反比关系，且更强的隔离作用可完全消除该反馈环路。本文还提出了一种验证该反馈环路存在的实验方法。进一步研究表明，当模型被瞬态信号激活时，级联的记忆性（即级联输出在信号移除后恢复至未刺激水平所需的总时间）由其激酶与磷酸酶之间的特定相互作用设计决定。
结论：
激酶与磷酸酶之间相互作用设计的差异，可差异化调控MAPK级联的鲁棒性与信号响应行为，而磷酸酶隔离可显著增强各型级联对扰动的鲁棒性。我们的分析揭示了一条隐性负反馈环路，且该负反馈环路的强度与磷酸酶隔离的强度呈负相关。响应瞬态信号的输出磷酸化持续时长，同样由对应级联的激酶-磷酸酶相互作用设计决定。

本模型已托管于BioModels数据库，编号为MODEL1204280029。
引用BioModels数据库的格式为：BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID: 20587024。
在适用法律允许的范围内，本编码模型的所有版权及相关或邻接权利已奉献至全球公共领域。更多信息请参阅[CC0公共领域贡献声明>http://creativecommons.org/publicdomain/zero/1.0/]。