Quantitative analysis of insulin-like growth factor 2 receptor and insulin-like growth factor binding proteins to identify control mechanisms for insulin-like growth factor 1 receptor phosphorylation.
Quantitative analysis of insulin-like growth factor 2 receptor and insulin-like growth factor binding proteins to identify control mechanisms for insulin-like growth factor 1 receptor phosphorylation.
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胰岛素样生长因子2受体和胰岛素样生长因子结合蛋白的定量分析，以鉴定胰岛素样生长因子1受体磷酸化的控制机制。
DOI：
10.1186/s12918-016-0263-6
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发表时间：
2016-02-09
影响因子：
--
通讯作者：
Kreeger PK
中科院分区：
文献类型：
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作者：
Tian D;Mitchell I;Kreeger PK
胰岛素样生长因子（IGF）系统通过调节增殖、分化和凋亡影响细胞发育，并且是癌症中有吸引力的治疗靶点。IGF系统是复杂的，具有两个配体（IGF 1，IGF 2），两个受体（IGF 1 R，IGF 2 R）和至少六个调节IGF配体生物利用度的高亲和力IGF结合蛋白（IGFBPs）。虽然对IGF系统的各个组成部分进行了深入研究，但这些不同组成部分如何整合为一个系统来调节细胞行为的问题尚不清楚。为了分析控制IGF网络活性的不同机制的相对重要性，我们开发了一个质量作用动力学模型，将细胞表面结合，磷酸化和细胞内运输事件。使用从OVCAR 5（一种永生化卵巢癌细胞系）收集的实验数据对模型进行校准和验证。然后，我们进行模型分析，以检查IGF 2 R或IGFBPs抵消IGF 1 R磷酸化的能力，这是IGF网络激活的关键步骤。该分析表明，IGF 2 R水平需要比IGF 1 R高320倍才能使pIGF 1 R降低25%，而IGFBP水平需要高390倍。癌症基因组图谱（TCGA）数据集的分析表明，这种水平的过度表达是不可能的IGF 2 R在卵巢癌，乳腺癌和结肠癌。相比之下，IGFBPs可能达到这些水平，这表明IGFBPs是IGF 1 R网络活性的更关键调节剂。磷酸化IGF 1 R水平对调节IGF 2 R网络臂的参数变化不敏感。使用质量作用动力学模型，我们确定IGF 2 R在各种条件下调节IGF 1 R的活性中起次要作用，并且由于其高表达水平，IGFBPs是调节IGF网络激活的主导机制。本文的在线版本（doi：10.1186/s12918-016-0263-6）包含补充材料，可供授权用户使用。
The insulin-like growth factor (IGF) system impacts cellular development by regulating proliferation, differentiation, and apoptosis, and is an attractive therapeutic target in cancer. The IGF system is complex, with two ligands (IGF1, IGF2), two receptors (IGF1R, IGF2R), and at least six high affinity IGF-binding proteins (IGFBPs) that regulate IGF ligand bioavailability. While the individual components of the IGF system are well studied, the question of how these different components integrate as a system to regulate cell behavior is less clear. To analyze the relative importance of different mechanisms that control IGF network activity, we developed a mass-action kinetic model incorporating cell surface binding, phosphorylation, and intracellular trafficking events. The model was calibrated and validated using experimental data collected from OVCAR5, an immortalized ovarian cancer cell line. We then performed model analysis to examine the ability of IGF2R or IGFBPs to counteract phosphorylation of IGF1R, a critical step for IGF network activation. This analysis suggested that IGF2R levels would need to be 320-fold greater than IGF1R in order to decrease pIGF1R by 25 %, while IGFBP levels would need to be 390-fold greater. Analysis of The Cancer Genome Atlas (TCGA) data set suggested that this level of overexpression is unlikely for IGF2R in ovarian, breast, and colon cancer. In contrast, IGFBPs can likely reach these levels, suggesting that IGFBPs are the more critical regulator of IGF1R network activity. Levels of phosphorylated IGF1R were insensitive to changes in parameters regulating the IGF2R arm of the network. Using a mass-action kinetic model, we determined that IGF2R plays a minor role in regulating the activity of IGF1R under a variety of conditions and that due to their high expression levels, IGFBPs are the dominant mechanism to regulating IGF network activation. The online version of this article (doi:10.1186/s12918-016-0263-6) contains supplementary material, which is available to authorized users.