Mathematical model of human growth hormone (hGH)-stimulated cell proliferation explains the efficacy of hGH variants as receptor agonists or antagonists
Mathematical model of human growth hormone (hGH)-stimulated cell proliferation explains the efficacy of hGH variants as receptor agonists or antagonists
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DOI：
10.1021/bp0499101
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发表时间：
2004-09-01
影响因子：
2.9
通讯作者：
Haugh, JM
中科院分区：
文献类型：
--
作者：
Haugh, JM
人生长激素（hGH）是一种治疗上重要的内分泌因子，其向各种细胞类型发出信号。在结构和功能上，hGH与其受体的相互作用已经得到了很好的解决，因此hGH和hGH受体变体实际上可以通过随机或合理的方法进行工程改造，以实现结合自由能的显著变化。hGH作用的一个独特特征是其两个hGH受体的同源二聚化，这是细胞内信号传导和刺激细胞增殖所必需的，但hGH突变体在基于细胞的测定中的效力很少与其总体受体结合亲和力相关。在这里，一个数学模型的生长激素刺激的细胞信号，会计不仅在细胞表面的结合相互作用，但诱导受体内吞和下调以及。受体内化通过限制活性受体复合物的寿命而影响配体效力，而与配体-受体结合性质无关。因此，该模型解释了，在定量方面，许多已发表的观察hGH受体激动和拮抗作用和挑战以前的研究，没有考虑受体运输作为一个中央调控机制的hGH信号的解释。
Human growth hormone (hGH) is a therapeutically important endocrine factor that signals various cell types . Structurally and functionally, the interactions of hGH with its receptor have been resolved in fine detail, such that hGH and hGH receptor variants can be practically engineered by either random or rational approaches to achieve significant changes in the free energies of binding. A somewhat unique feature of hGH action is its homodimerization of two hGH receptors, which is required for intracellular signaling and stimulation of cell proliferation, yet the potencies of hGH mutants in cell-based assays rarely correlate with their overall receptor-binding avidities. Here, a mathematical model of hGH-stimulated cell signaling is posed, accounting not only for binding interactions at the cell surface but induction of receptor endocytosis and downregulation as well. Receptor internalization affects ligand potency by imposing a limit on the lifetime of an active receptor complex, irrespective of ligand-receptor binding properties. The model thus explains, in quantitative terms, the numerous published observations regarding hGH receptor agonism and antagonism and challenges the interpretations of previous studies that have not considered receptor trafficking as a central regulatory mechanism in hGH signaling.