Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma.
Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma.
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G蛋白偶联受体（gpcr）是人类最大的基因家族，是信号通路的重要调节因子。然而，对它们基因变化的了解是有限的。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分析了黑色素瘤中734个gpcr的突变状态。该调查发现，家族成员GRM3经常发生突变，其中一个突变聚集在一个位置。对GRM3变化的生化分析表明，突变体GRM3选择性地调节MEK的磷酸化，导致不依赖锚定的生长和迁移增加。表达突变体GRM3的黑色素瘤细胞在短发夹rna介导的GRM3敲低或使用选择性MEK抑制剂AZD-6244治疗后，细胞生长和细胞迁移减少，AZD-6244目前正在2期临床试验中使用。我们的研究产生了GPCR基因家族中最全面的遗传改变图谱。
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.
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