A novel dysfunctional growth hormone variant (Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway.
A novel dysfunctional growth hormone variant (Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway.
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DOI：
10.1210/jc.2003-030652
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发表时间：
2004-03
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通讯作者：
Mark D. Lewis;M. Horan;D. Millar;V. Newsway;T. Easter;L. Fryklund;J. Gregory;M. Norin;C.J. Del Valle;J. López-Siguero;R. Cañete;L. F. López-Canti;Nieves Díaz-Torrado;R. Espino;À. Ulied;M. Scanlon;A. Procter;D. Cooper
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作者：
Mark D. Lewis;M. Horan;D. Millar;V. Newsway;T. Easter;L. Fryklund;J. Gregory;M. Norin;C.J. Del Valle;J. López-Siguero;R. Cañete;L. F. López-Canti;Nieves Díaz-Torrado;R. Espino;À. Ulied;M. Scanlon;A. Procter;D. Cooper
对74名家族性身材矮小的儿童进行了垂体表达GH1基因的突变筛选。发现了两个新的突变：Ile179Met替代和-360A- >g启动子变异。Ile179Met变体显示出与野生型GH相似程度的蛋白水解抗性，这表明Met的引入不会导致显著的错误折叠。大鼠垂体细胞分泌Ile179Met GH也与野生型相似。虽然受体结合研究没有显示出结合特性的差异，但分子模拟研究表明，Ile179Met取代可能会干扰GH与含有热点残基Trp169的GH受体环之间的相互作用，从而影响信号转导。因此，我们研究了Ile179Met变体激活信号传感器和转录激活因子（STAT） 5应答荧光素酶报告基因并诱导STAT 5和ERK磷酸化的能力。与正常激活STAT 5的能力相反，Ile179Met变体对ERK的激活减少到野生型的一半。虽然突变受体激动剂对不同信号通路激活的不同影响是前所未有的，但这些发现也表明ERK通路可能在介导GH的作用中发挥作用。
The pituitary-expressed GH1 gene was screened for mutation in a group of 74 children with familial short stature. Two novel mutations were identified: an Ile179Met substitution and a -360A-->G promoter variant. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant misfolding. Secretion of Ile179Met GH from rat pituitary cells was also similar to that of wild type. Although receptor binding studies failed to show any difference in binding characteristics, molecular modeling studies suggested that the Ile179Met substitution might nevertheless perturb interactions between GH and the GH receptor loop containing the hotspot residue Trp169, thereby affecting signal transduction. The ability of the Ile179Met variant to activate a signal transducer and activator of transcription (STAT) 5-responsive luciferase reporter gene and induce phosphorylation of STAT 5 and ERK was therefore studied. In contrast to its ability to activate STAT 5 normally, activation of ERK by the Ile179Met variant was reduced to half that observed with wild type. Although differential effects on the activation of distinct signaling pathways by a mutant receptor agonist are unprecedented, these findings also suggest that the ERK pathway could play a role in mediating the action of GH.