Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma

Todd D. Prickett, Xiaomu Wei, Isabel Cardenas-Navia, Jamie K. Teer, Jimmy C. Lin, Vijay Walia, Jared Gartner, Jiji Jiang, Praveen F. Cherukuri, Alfredo Molinolo, Michael A. Davies, Jeffrey E. Gershenwald, Katherine Stemke-Hale, Steven A. Rosenberg, Elliott H. Margulies, Yardena Samuels

Research output: Contribution to journalArticlepeer-review

Abstract

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 RNAĝ€"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.

Original languageEnglish (US)
Pages (from-to)1119-1126
Number of pages8
JournalNature genetics
Volume43
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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