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The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer

Nature Reviews Cancer volume 13, pages 412–424 (2013)Cite this article

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Key Points

  • Recent cancer genome deep sequencing efforts have revealed an unanticipated high frequency of mutations in G proteins and G-protein-coupled receptors (GPCRs) in most tumour types.

  • A striking 4.2% of all tumour sequences deposited to date show activating mutations in GNAS (a complex locus that encodes Gαs). Transforming mutations in GNAS have been well documented in human thyroid and pituitary tumours, and recent sequencing efforts have shown these mutations to be present in a wide variety of additional tumour types, including colon cancer, hepatocellular carcinoma, and parathyroid, ovarian, endometrial, biliary tract and pancreatic tumours.

  • Mutually exclusive activating mutations in GNAQ or GNA11 (encoding Gαq family members) occur in 5.6% of tumours, and they are present in ∼66% and ∼6% of melanomas arising in the eye and skin, respectively, where they can act as driver oncogenes.

  • Hotspot mutations in Gαs (R201 and Q227) as well as Gαq and Gα11 (R183 and Q209) disrupt the GTPase activity, thereby leading to constitutive activity and persistent signalling.

  • Nearly 20% of human cancers harbour mutations in GPCRs.

  • The most frequently mutated GPCRs include thyroid-stimulating hormone receptor (TSHR), Smoothened (SMO), glutamate metabotropic receptors (GRMs), members of the adhesion family of GPCRs and receptors for bioactive lipid mediators such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) that accumulate in the tumour microenvironment.

  • Many GPCR mutations are still uncharacterized with respect to their potential contribution to tumorigenesis and cancer progression.

  • Aberrant expression, overexpression or signal reprogramming of GPCRs and G proteins in tumour cells can contribute to cancer development and progression. These alterations may arise from cancer-specific changes in gene copy number, as well as from other genetic, epigenetic and post-translational changes resulting in higher protein expression, thereby enhancing tumour progression and metastasis.

  • Detailed three dimensional structures of GPCRs in various activation states can now help to explain the functional impact of cancer-associated GPCR mutations, and guide the rational design of signalling-selective GPCR agonists, antagonists and allosteric modulators.

  • G proteins, GPCRs and their linked signalling circuitry represent novel therapeutic targets for cancer prevention and treatment.

Abstract

Aberrant expression and activity of G proteins and G-protein-coupled receptors (GPCRs) are frequently associated with tumorigenesis. Deep sequencing studies show that 4.2% of tumours carry activating mutations in GNAS (encoding Gαs), and that oncogenic activating mutations in genes encoding Gαq family members (GNAQ or GNA11) are present in ∼66% and ∼6% of melanomas arising in the eye and skin, respectively. Furthermore, nearly 20% of human tumours harbour mutations in GPCRs. Many human cancer-associated viruses also express constitutively active viral GPCRs. These studies indicate that G proteins, GPCRs and their linked signalling circuitry represent novel therapeutic targets for cancer prevention and treatment.

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Figure 1: Cancer-related mutations in human TSHR projected onto a three-dimensional model.
Figure 2: The residue positions most frequently mutated in cancers in the context of different functional states of the G protein α-subunits.

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Acknowledgements

The mutation data were obtained from the Wellcome Trust Sanger Institute COSMIC web site. This work was supported by the Intramural Research Program of the US National Institutes of Health and the US National Institute of Dental and Craniofacial Research (to J.S.G. and M.O.), extramural grants U01 GM094612 and partial funding from R01 GM071872 and U54 GM094618 (to T.M.H. and I.K.) and grant 152434 from Consejo Nacional de Ciencia y Tecnología (CONACyT, Mexico) (to J.V.P.).

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Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Morgan O'Hayre & J. Silvio Gutkind

  2. Department of Pharmacology, CINVESTAV-IPN, Av. Instituto Politcnico Nacional 2508, Col. San Pedro Zacatenco, C.P. 07360, México

    José Vázquez-Prado

  3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, 92093, California, USA

    Irina Kufareva & Tracy M. Handel

  4. Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Eric W. Stawiski & Somasekar Seshagiri

  5. Department of Bioinformatics and Computational Biology, Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Eric W. Stawiski

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This work was supported by the Intramural Research Program of the US National Institutes of Health, the US National Institute of Dental and Craniofacial Research (to J.S.G. and M.O.) as well as extramural grants U01 GM094612, and partial funding from R01 GM071872, and U54 GM094618 (to T.M.H. and I.K.); and grant 152434 from Consejo Nacional de Ciencia y Tecnología (CONACyT, Mexico) (to J.V.P.).

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Supplementary information

Supplementary information S1 (table)

Frequency of somatic mutation in G protein subunits and G protein coupled receptors (GPCRs). (XLS 275 kb)

Supplementary information S2 (table)

G protein and G protein coupled receptors (GPCRs) genes with a significant number of mutations relative to their respective tissue type background mutation rate. (XLS 69 kb)

Supplementary information S3 (table)

G Protein and G protein coupled receptor (GPCR) hotspot mutations. (XLS 121 kb)

Supplementary information S4 (table)

Complete list of G Protein and G protein coupled receptor (GPCR) somatic mutants reported in cancer. (XLSX 1546 kb)

Glossary

G-protein-coupled receptors

(GPCRs). A family of receptor proteins that have seven-transmembrane domains, an extracellular amino terminus and an intracellular carboxyl terminus. They respond to stimuli outside the cell and transduce signals into the cells through interactions with intracellular signalling proteins, including G proteins.

G proteins

A family of guanine-nucleotide-binding proteins that are important for signal transduction. Their activity is regulated by binding and hydrolysing GTP such that the active state is GTP-bound, whereas the inactive form is in a GDP-bound state. Heterotrimeric G proteins consist of α-, β- and γ-subunits.

Regulators of G protein signalling

(RGS). GTPase-accelerating proteins that lead to heterotrimeric G protein inactivation by promoting hydrolysis of the GTP of G to GDP.

Arrestins

A family of proteins that interact with the carboxyl termini of G-protein-coupled receptors and help to mediate receptor desensitization, internalization, recycling and signalling.

Guanine-nucleotide exchange factors

(GEFs). Proteins that stimulate the release of GDP to allow exchange for GTP, thereby promoting G protein activation.

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O'Hayre, M., Vázquez-Prado, J., Kufareva, I. et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat Rev Cancer 13, 412–424 (2013). https://doi.org/10.1038/nrc3521

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