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Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor

机译：建模信号线蛋白向胰岛素样生长因子1受体的细胞系特异性募集

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摘要

Receptor tyrosine kinases (RTKs) typically contain multiple autophosphorylation sites in their cytoplasmic domains. Once activated, these autophosphorylation sites can recruit downstream signaling proteins containing Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine-containing short linear motifs (SLiMs). These domains and SLiMs have polyspecific or promiscuous binding activities. Thus, multiple signaling proteins may compete for binding to a common SLiM and vice versa. To investigate the effects of competition on RTK signaling, we used a rule-based modeling approach to develop and analyze models for ligand-induced recruitment of SH2/PTB domain-containing proteins to autophosphorylation sites in the insulin-like growth factor 1 (IGF1) receptor (IGF1R). Models were parameterized using published datasets reporting protein copy numbers and site-specific binding affinities. Simulations were facilitated by a novel application of model restructuration, to reduce redundancy in rule-derived equations. We compare predictions obtained via numerical simulation of the model to those obtained through simple prediction methods, such as through an analytical approximation, or ranking by copy number and/or KD value, and find that the simple methods are unable to recapitulate the predictions of numerical simulations. We created 45 cell line-specific models that demonstrate how early events in IGF1R signaling depend on the protein abundance profile of a cell. Simulations, facilitated by model restructuration, identified pairs of IGF1R binding partners that are recruited in anti-correlated and correlated fashions, despite no inclusion of cooperativity in our models. This work shows that the outcome of competition depends on the physicochemical parameters that characterize pairwise interactions, as well as network properties, including network connectivity and the relative abundances of competitors.
机译：受体酪氨酸激酶（RTK）通常在其胞质结构域中包含多个自磷酸化位点。一旦激活，这些自磷酸化位点就可以募集含有Src同源性2（SH2）和磷酸酪氨酸结合（PTB）域的下游信号蛋白，它们识别含有磷酸酪氨酸的短线性基序（SLiMs）。这些结构域和SLiM具有多特异性或混杂结合活性。因此，多种信号蛋白可以竞争结合共同的SLiM，反之亦然。若要调查竞争对RTK信号的影响，我们使用了基于规则的建模方法来开发和分析用于由配体诱导的包含SH2 / PTB域的蛋白质向胰岛素样生长因子1（IGF1）的自磷酸化位点募集的模型受体（IGF1R）。使用发布的数据集参数化模型，该数据集报告蛋白质拷贝数和位点特异性结合亲和力。通过模型重构的新颖应用来简化仿真，以减少规则衍生方程式中的冗余。我们将通过模型的数值模拟获得的预测与通过简单的预测方法（例如，通过解析近似或通过拷贝数和/或KD值进行排名）获得的预测进行比较，发现简单的方法无法概括数字的预测模拟。我们创建了45个细胞系特异性模型，这些模型证明了IGF1R信号传导中的早期事件如何依赖于细胞的蛋白质丰度概况。通过模型重组，模拟得到了以反相关和相关方式招募的成对的IGF1R结合伴侣，尽管我们的模型中没有包括合作性。这项工作表明，竞争的结果取决于表征成对相互作用的理化参数以及网络特性，包括网络连接性和竞争者的相对丰度。

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