Diverse biochemical properties of Shp2 mutants
Diverse biochemical properties of Shp2 mutants
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DOI：
10.1074/jbc.m504699200
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发表时间：
2005-09-02
影响因子：
4.8
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Keilhack, H;David, FS;Neel, BG
Src同源性2 (SH2)-含蛋白-酪氨酸磷酸酶Shp2 （PTPN11）的突变是半数常染色体显性遗传疾病Noonan综合征的基础，在一些血液学和实体恶性肿瘤中发现了体细胞Shp2突变。早期对少量突变的研究表明，与疾病相关的突变引起构成型（不依赖于SH2结合）激活，而与癌症相关的突变比与努南综合征相关的突变更活跃。我们对一组更大的Shp2突变体进行了表征，发现这种“以活性为中心”的模型不能解释所有致病性Shp2突变的行为。相反，酶、结构和数学模型分析表明，这些突变可以不同程度地影响基础活化、SH2结构域磷酸肽亲和力和/或底物特异性。此外，突变体的基础激活程度与其诱导的疾病之间没有绝对的相关性。我们提出，活化的Shp2突变体调节从特定刺激到一部分效应物的信号传导，并为理解Shp2活化、细胞内信号传导和病理之间的复杂关系提供了理论框架。
Mutations in the Src homology 2 ( SH2)- containing protein- tyrosine phosphatase Shp2 ( PTPN11) underlie half of the cases of the autosomal dominant genetic disorder Noonan syndrome, and somatic Shp2 mutations are found in several hematologic and solid malignancies. Earlier studies of small numbers of mutants suggested that disease- associated mutations cause constitutive ( SH2 binding- independent) activation and that cancer- associated mutants are more active than those associated with Noonan syndrome. We have characterized a larger panel of Shp2 mutants and find that this " activity- centric" model cannot explain the behaviors of all pathogenic Shp2 mutations. Instead, enzymatic, structural, and mathematical modeling analyses show that these mutants can affect basal activation, SH2 domain phosphopeptide affinity, and/ or substrate specificity to varying degrees. Furthermore, there is no absolute correlation between the mutants' extents of basal activation and the diseases they induce. We propose that activated mutants of Shp2 modulate signaling from specific stimuli to a subset of effectors and provide a theoretical framework for understanding the complex relationship between Shp2 activation, intracellular signaling, and pathology.