Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Bethesda, Maryland, USA.
Nat Genet. 2011 Sep 25;43(11):1119-26. doi: 10.1038/ng.950.
G protein-coupled receptors (GPCRs), the largest human gene family, are important regulators of signaling pathways. However, knowledge of their genetic alterations is limited. In this study, we used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 GPCRs in melanoma. This investigation revealed that one family member, GRM3, was frequently mutated and that one of its mutations clustered within one position. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MEK, leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor, AZD-6244, which is currently being used in phase 2 clinical trials. Our study yields the most comprehensive map of genetic alterations in the GPCR gene family.
G 蛋白偶联受体（GPCRs）是人类最大的基因家族，是信号通路的重要调节剂。然而，它们的遗传改变的知识是有限的。在这项研究中，我们使用外显子捕获和大规模平行测序方法来分析黑色素瘤中 734 种 GPCR 的突变状态。这项研究表明，一个家族成员 GRM3 经常发生突变，其一个突变簇位于一个位置。GRM3 改变的生化分析表明，突变的 GRM3 选择性地调节 MEK 的磷酸化，导致锚定非依赖性生长和迁移增加。表达突变 GRM3 的黑色素瘤细胞在短发夹 RNA 介导的 GRM3 敲低或用选择性 MEK 抑制剂 AZD-6244 处理后，细胞生长和细胞迁移减少，AZD-6244 目前正在进行 2 期临床试验。我们的研究提供了 GPCR 基因家族遗传改变的最全面图谱。
