title: Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma.
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 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.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.forename: Isabel
authors.initials: I
authors.lastname: Cardenas-Navia
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Jimmy C
authors.initials: JC
authors.lastname: Lin
authors.forename: Vijay
authors.initials: V
authors.lastname: Walia
authors.forename: Jared
authors.initials: J
authors.lastname: Gartner
authors.forename: Jiji
authors.initials: J
authors.lastname: Jiang
authors.forename: Praveen F
authors.initials: PF
authors.lastname: Cherukuri
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Margulies
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D005091:Exons; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: D043562:Receptors, G-Protein-Coupled