A Novel Y332C Missense Mutation in the Intracellular Domain of The Human Growth Hormone Receptor Does Not Alter STAT5b Signaling: Redundancy of GHR Intracellular Tyrosines Involved in STAT5b Signaling
A Novel Y332C Missense Mutation in the Intracellular Domain of The Human Growth Hormone Receptor Does Not Alter STAT5b Signaling: Redundancy of GHR Intracellular Tyrosines Involved in STAT5b Signaling
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DOI：
10.1159/000320461
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发表时间：
2011-01-01
影响因子：
3.2
通讯作者：
Rosenfeld, Ron G.
中科院分区：
文献类型：
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作者：
Derr, Michael A.;Fang, Peng;Rosenfeld, Ron G.
背景资料：生长激素受体（GHR）与GH结合后，诱导JAK 2介导的GHR细胞内酪氨酸磷酸化，然后募集STAT 5 b。由于GHR或STAT 5 b基因突变导致的STAT 5 b信号传导异常导致对GH反应不良和严重身材矮小。目的：评价并比较在身材矮小患者中鉴定的新型Y332 C GHR变体与其他GHR细胞内酪氨酸在GHR-STAT 5 b信号传导过程中的作用。结果如下：重组人GHR构建体携带Y332 C或7个细胞内酪氨酸中的每一个的单个Y到F变化，在重建研究中不改变GH诱导的GHR-STAT 5 b信号传导。然而，GH诱导的STAT 5 b活化在所有7个酪氨酸失活的hGHR变体（MYF）中被特异性废除。当评估携带单个细胞内酪氨酸的hGHR变体时，STAT 5 b活化与仅具有携带Y 534、Y 566或Y 627的变体的野生型hGHR相当。结论：我们提供的证据表明，在人GHR中，3个细胞内酪氨酸在GH诱导的STAT 5 b信号转导过程中是关键的和冗余的。这种冗余可以解释为什么Y332 C变体没有改变STAT 5 b信号传导。人GHR胞内结构域错义变异的鉴定应谨慎解释并严格分析。版权所有（C）2010 S. Karger AG，巴塞尔
Background: The growth hormone receptor (GHR), upon binding with GH, induces JAK2-mediated phosphorylation of GHR intracellular tyrosines, which then recruit STAT5b. Aberrancies in STAT5b signaling, due to mutations in GHR or STAT5b genes, result in poor responses to GH and severe short stature. Objective: To evaluate and compare the role of a novel Y332C GHR variant identified in a patient with short stature to the other GHR intracellular tyrosines in the GHR-STAT5b signaling process. Results: Recombinant human GHR constructs carrying Y332C or single Y to F changes for each of the 7 intracellular tyrosines did not alter GH-induced GHR-STAT5b signaling in reconstitution studies. However, GH-induced STAT5b activation was specifically abrogated in an hGHR variant in which all 7 tyrosines were inactivated (MYF). When hGHR variants carrying single intracellular tyrosines were evaluated, STAT5b activation was comparable to that of wild-type hGHR only with variants carrying Y534, Y566 or Y627. Conclusion: We provide evidence that in human GHR, 3 intracellular tyrosines are critical and redundant in the GH-induced STAT5b signaling process. This redundancy may explain why an Y332C variant did not alter STAT5b signaling. Identification of missense variants in human GHR intracellular domain should be interpreted with caution and rigorously analyzed. Copyright (C) 2010 S. Karger AG, Basel