TY - JOUR
T1 - Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma
AU - Prickett, Todd D.
AU - Wei, Xiaomu
AU - Cardenas-Navia, Isabel
AU - Teer, Jamie K.
AU - Lin, Jimmy C.
AU - Walia, Vijay
AU - Gartner, Jared
AU - Jiang, Jiji
AU - Cherukuri, Praveen F.
AU - Molinolo, Alfredo
AU - Davies, Michael A.
AU - Gershenwald, Jeffrey E.
AU - Stemke-Hale, Katherine
AU - Rosenberg, Steven A.
AU - Margulies, Elliott H.
AU - Samuels, Yardena
N1 - Funding Information:
We thank S. Gutkind, J. Cronin, H. Abaan, P. Cruz, J. Mullikin, N. Hansen and members of the US National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program for generating the sequence data analyzed here. We thank S. Hoogstraten-Miller and I. Ginty for assistance with the mouse experiments and S. Anderson for assistance with FACS analysis. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, US National Institutes of Health, USA. Grant support was also provided by the University of Texas MD Anderson Cancer Center Melanoma Informatics, Tissue Resource and Pathology Core and the Melanoma Specialized Programs of Research Excellence (P50 CA93459). M.A.D. is supported by funding from the Melanoma Research Alliance, the American Society of Clinical Oncology and the MD Anderson Physician-Scientist Program. A.M. is supported by the Intramural Research program of the National Institute of Dental and Craniofacial Research, NIH.
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.950
DO - 10.1038/ng.950
M3 - Article
C2 - 21946352
AN - SCOPUS:80054997116
SN - 1061-4036
VL - 43
SP - 1119
EP - 1126
JO - Nature genetics
JF - Nature genetics
IS - 11
ER -