Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes.
Endosomal receptor kinetics determine the stability of intracellular growth factor signalling complexes.
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内体受体动力学决定细胞内生长因子信号复合物的稳定性。
DOI：
10.1042/bj20060756
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Edelman,ElazerR
中科院分区：
文献类型：
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作者：
Tzafriri,ARami;Edelman,ElazerR
有一种新兴的范式认为，生长因子信号在内体中持续存在，并且细胞对生长因子的反应是由细胞表面和内体事件的整合来定义的。由于内体中激活的受体暴露于一组不同的结合配偶体，因此与位于细胞表面时相比，它们可能会引发不同的信号。因此，对生长因子信号传导的完整理解需要了解细胞表面和内体中的生长因子-受体结合和运输动力学。生长因子与表面受体的结合已得到很好的表征，如果考虑到 pH 值的变化，则假定内体结合遵循表面动力学。然而，内体内的特异性结合动力学尚未得到详细研究。为了解析控制内体受体结合状态的因素，我们分析了表皮生长因子受体运输和结合的全细胞数学模型。我们发现内体内生长因子-受体复合物的稳定性由三个主要的独立因素控制：内体解离常数、内体总体积和内体受体的数量。这些因子被组合成一个无量纲参数，该参数决定生长因子-受体复合物的内体结合状态，并且可以区分不同的生长因子彼此和不同的细胞状态。我们的研究结果表明，不能仅根据解离常数的 pH 依赖性来评估内体区室中生长因子的结合，还必须考虑内体区室中受体的浓度。
There is an emerging paradigm that growth factor signalling continues in the endosome and that cell response to a growth factor is defined by the integration of cell surface and endosomal events. As activated receptors in the endosome are exposed to a different set of binding partners, they probably elicit differential signals compared with when they are at the cell surface. As such, complete appreciation of growth factor signalling requires understanding of growth factor–receptor binding and trafficking kinetics both at the cell surface and in endosomes. Growth factor binding to surface receptors is well characterized, and endosomal binding is assumed to follow surface kinetics if one accounts for changes in pH. Yet, specific binding kinetics within the endosome has not been examined in detail. To parse the factors governing the binding state of endosomal receptors we analysed a whole-cell mathematical model of epidermal growth factor receptor trafficking and binding. We discovered that the stability of growth factor–receptor complexes within endosomes is governed by three primary independent factors: the endosomal dissociation constant, total endosomal volume and the number of endosomal receptors. These factors were combined into a single dimensionless parameter that determines the endosomal binding state of the growth factor–receptor complex and can distinguish different growth factors from each other and different cell states. Our findings indicate that growth factor binding within endosomal compartments cannot be appreciated solely on the basis of the pH-dependence of the dissociation constant and that the concentration of receptors in the endosomal compartment must also be considered.