Rare cancer-specific mutations in PIK3CA show gain of function
Rare cancer-specific mutations in PIK3CA show gain of function
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DOI：
10.1073/pnas.0701005104
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发表时间：
2007-03-27
影响因子：
11.1
通讯作者：
Vogt, Peter K.
中科院分区：
文献类型：
--
作者：
Gymnopoulos, Marco;Elsliger, Marc-Andre;Vogt, Peter K.
PIK3CA 是编码磷脂酰肌醇 3 激酶 (PI3K) 催化亚基 p110 α 的基因，对 15 个罕见的癌症衍生突变体的生物学和生化特性进行了检查。其中 14 个突变体显示出功能增强：它们诱导鸡胚成纤维细胞发生雷帕霉素敏感的致癌转化，组成型激活 Akt 和 TOR 介导的信号传导，并显示出增强的脂质激酶活性。这些突变体在 p110a 部分结构模型上的映射表明存在三组突变体，根据它们在蛋白质不同功能域中的位置来定义。我们假设这三组中的每一个都通过不同的分子机制诱导 PI3K 功能的增强。 C2 结构域中的突变体增加了该结构域的表面正电荷，因此可能会增强 p110 α 向细胞膜的募集。螺旋结构域中的突变体映射到蛋白质的连续表面，并可能影响与其他蛋白质的相互作用。激酶结构域中的突变体位于激活环的铰链附近。它们可能会改变激活环的位置和移动性。任意引入的突变在蛋白质内部没有可检测的表型图谱，或者位于与包含功能获得突变体的暴露表面相对的表面区域。将关键表面上的酸性或中性残基交换为碱性残基的工程突变体显示出功能的增强。
Fifteen rare cancer-derived mutants of PIK3CA, the gene coding for the catalytic subunit p110 alpha of phosphatidylinositol 3-kinase (PI3K), were examined for their biological and biochemical properties. Fourteen of these mutants show a gain of function: they induce rapamycin-sensitive oncogenic transformation of chicken embryo fibroblasts, constitutively activate Akt and TOR-mediated signaling, and show enhanced lipid kinase activity. Mapping of these mutants on a partial structural model of p110a suggests three groups of mutants, defined by their location in distinct functional domains of the protein. We hypothesize that each of these three groups induces a gain of PI3K function by a different molecular mechanism. Mutants in the C2 domain increase the positive surface charge of this domain and therefore may enhance the recruitment of p110 alpha to cellular membranes. Mutants in the helical domain map to a contiguous surface of the protein and may affect the interaction with other protein(s). Mutants in the kinase domain are located near the hinge of the activation loop. They may alter the position and mobility of the activation loop. Arbitrarily introduced mutations that have no detectable phenotype map either to the interior of the protein or are positioned on a surface region that lies opposite to the exposed surfaces containing gain-of-function mutants. Engineered mutants that exchange acidic or neutral residues for basic residues on the critical surfaces show a gain of function.