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首页> 外文期刊>Biochemistry >Biochemical basis for the functional switch that regulates hepatocyte growth factor receptor tyrosine kinase activation
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Biochemical basis for the functional switch that regulates hepatocyte growth factor receptor tyrosine kinase activation

机译：调节肝细胞生长因子受体酪氨酸激酶活化的功能开关的生物化学基础

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摘要

Ligand-induced dimerization of receptor tyrosine kinases (RTKs) modulates a system of linked biochemical reactions, sharply switching the RTK from a quiescent state to an active state that becomes phosphorylated and triggers intracellular signaling pathways. To improve our understanding of this molecular switch, we developed a quantitative model for hepatocyte growth factor receptor (c-MET) activation using parameters derived in large part from c-MET kinetic and thermodynamic experiments. Our model accurately produces the qualitative and quantitative dynamic features of c-MET phosphorylation observed in cells following ligand binding, including a rapid transient buildup of phosphorylated c-MET at high ligand concentrations. In addition, our model predicts a slow buildup of phosphorylated c-MET under conditions of reduced phosphatase activity and no extracellular agonist. Significantly, this predicted response is observed in cells treated with phosphatase inhibitors, further validating our model. Parameter sensitivity studies clearly show that synergistic oligomerization-dependent changes in c-MET kinetic, thermodynamic, and dephosphorylation properties result in the selective activation of the dimeric receptor, confirming that this model can be used to accurately evaluate the relative importance of linked biochemical reactions important for c-MET activation. Our model suggests that the functional differences observed between c-MET monomers and dimers may have incrementally evolved to optimize cell surface signaling responses.
机译：配体诱导的受体酪氨酸激酶（RTK）的二聚化调节连接的生物化学反应的系统，将RTK从静态状态急剧切换到活性状态，该活性状态变得磷酸化并触发细胞内信号传导途径。为了提高我们对该分子开关的理解，我们使用大部分来自C-Met动力学和热力学实验的参数开发了肝细胞生长因子受体（C-MET）活化的定量模型。我们的模型在配体结合后，在细胞中观察到的C-Met磷酸化的定性和定量动态特征，包括在高配体浓度下快速瞬时积聚的磷酸化C-Met。此外，我们的模型在降低的磷酸酶活性和细胞外激动剂的条件下预测磷酸化C-Met的缓慢累积。值得注意的是，在用磷酸酶抑制剂处理的细胞中观察到该预测反应，进一步验证我们的模型。参数敏感性研究清楚地表明，C-Met动力学，热力学和去磷酸化性质的协同寡聚化依赖性变化导致二聚体受体的选择性活化，证实该模型可用于准确评估链接的生化反应的相对重要性用于C-MET激活。我们的模型表明，C-Met单体和二聚体之间观察到的功能差可以逐渐地发展以优化细胞表面信号调速。

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