Mutational analysis of the tyrosine phosphatome in colorectal cancers
Mutational analysis of the tyrosine phosphatome in colorectal cancers
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DOI：
10.1126/science.1096096
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发表时间：
2004-05-21
期刊：
影响因子：
56.9
通讯作者：
Velculescu, VE
中科院分区：
文献类型：
--
作者：
Wang, ZH;Shen, D;Velculescu, VE
酪氨酸磷酸化受蛋白酪氨酸磷酸酶（PTPs）和激酶（PTKs）的调节，在肿瘤发生的信号通路中起重要作用。对人类癌症中酪氨酸磷酸酶基因超家族的突变分析确定了6种PTP（PTPRF、PTPRG、PTPRT、PTPN 3、PTPN 13、PTPN 14）中的83种体细胞突变，影响26%的结直肠癌和一小部分肺癌、乳腺癌和胃癌。15个突变是无义、移码或剪接位点改变，预测会导致缺乏磷酸酶活性的截短蛋白。五个错义突变在最常见的改变PTP（PTPRT）进行了生化检查，发现降低磷酸酶活性。野生型而非突变型PTPRT在人癌细胞中的表达抑制细胞生长。这些观察结果表明，突变的酪氨酸磷酸酶是肿瘤抑制基因，调节细胞途径，可能是顺从的治疗干预。
Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice-site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP ( PTPRT) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.