A mutant signal transducer and activator of transcription 5b, associated with growth hormone insensitivity and insulin-like growth factor-I deficiency, cannot function as a signal transducer or transcription factor
A mutant signal transducer and activator of transcription 5b, associated with growth hormone insensitivity and insulin-like growth factor-I deficiency, cannot function as a signal transducer or transcription factor
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DOI：
10.1210/jc.2005-2558
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发表时间：
2006-04-01
影响因子：
5.8
通讯作者：
Rosenfeld, RG
中科院分区：
文献类型：
--
作者：
Fang, P;Kofoed, EM;Rosenfeld, RG
内容：一个自然的错义突变的信号转导和转录激活因子（STAT）5 b基因最近被确定与一名女性患者表现出严重的生长障碍和免疫功能障碍。该突变导致src-同源性-2结构域中残基630（A630 P）处的丙氨酸取代为脯氨酸，该结构域是STAT与活化受体上的磷酸酪氨酸对接、STAT二聚化和磷酸-STAT-DNA相互作用的稳定所必需的区域。本研究的目的是探讨A630 P-1基因引起GH不敏感和IGF-I缺乏的分子机制。结果：在使用HEK 293细胞的重建实验中，GH和干扰素-γ都不能激活突变体STAT 5 b（A630 P），如通过缺乏免疫可检测的磷酸-酪氨酰-STAT 5 b（A630 P）和不能驱动荧光素酶报告子活性所证明的。然而，Src家族的非受体激酶[组成型活性v-src和上皮生长因子诱导的c-src]酪氨酸磷酸化STAT 5 b（A630 P）。v-src诱导的磷酸化STAT 5 b（A630 P）易位到细胞核，但与野生型Stat 5 b不同，不能结合DNA.Conclusions：A630 P突变破坏了src同源性2结构，使得：1）突变型STAT 5 b最有可能无法对接到配体激活受体上的磷酸化酪氨酸; 2）与DNA的稳定相互作用被阻止。由于STAT 5 b（A630 P）是一种低效的信号转导和转录因子，对正常生长和免疫重要的信号通路的不利影响部分解释了GH不敏感和免疫功能障碍的复杂临床表型。
Context: A natural missense mutation in the signal transducer and activator of transcription ( STAT) 5b gene was recently identified in association with a female patient presenting with severe growth failure and immune dysfunction. The mutation results in an alanine to proline substitution at residue 630 (A630P) in the src-homology-2 domain, a region essential for docking of STATs to phospho-tyrosines on activated receptors, STAT dimerization, and stabilization of phospho-STAT-DNA interactions.Objective: The purpose of this study was to explore the molecular mechanisms underlying the GH insensitivity and IGF-I deficiency caused by the A630P-mutated STAT5b.Results: In reconstitution experiments using HEK293 cells, both GH and interferon-gamma were unable to activate mutant STAT5b ( A630P), as demonstrated by lack of immunodetectable phospho-tyrosyl-STAT5b A630P) and inability to drive luciferase reporter activity. However, the Src family of nonreceptor kinases [ constitutively active v-src and epithelial growth factor-induced c-src] tyrosine-phosphorylated STAT5b(A630P). The v-src-induced phospho-STAT5b(A630P) translocated to the nucleus but, unlike wild-type Stat5b, was unable to bind DNA.Conclusions: The A630P mutation disrupts the src-homology-2 architecture such that: 1) mutant STAT5b most likely cannot dock to phospho-tyrosines on ligand-activated receptors; and 2) stable interactions with DNA are prevented. Because STAT5b ( A630P) is an inefficient signal transducer and transcription factor, the detrimental impact on signaling pathways important for normal growth and immunity explains, in part, the complex clinical phenotype of GH insensitivity and immune dysfunction.