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The Emerging Mutational Landscape of G Proteins and G-Protein-Coupled

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The Emerging Mutational Landscape of G Proteins and G-Protein-Coupled ANALYSIS The emerging mutational landscape of G proteins and G‑protein‑coupled receptors in cancer Morgan O’Hayre1, José Vázquez-Prado2, Irina Kufareva3, Eric W. Stawiski4,5, Tracy M. Handel3, Somasekar Seshagiri4 and J. Silvio Gutkind1 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. The G-protein-coupled receptor (GPCR) family of proteins G protein and GPCR signalling comprises approximately 4% of the encoded human genes: The widely accepted model for GPCR activation involves 1Oral and Pharyngeal Cancer Branch, Dental and with over 800 members, it is the largest family of cell- the binding of an agonist ligand at the extracellular side Craniofacial Research, surface receptors involved in signal transduction. These of the receptor, which induces a conformational change in National Institutes of Health, proteins are characterized by a seven-transmembrane the receptor and alters the position of its transmembrane Bethesda, Maryland 20892, domain structure with an extracellular amino terminus helices and intracellular loops. In this active conforma- USA. and an intracellular carboxyl terminus. GPCRs have tion, the agonist-occupied receptor couples to the hetero- 2Department of Pharmacology, CINVESTAV- crucial roles in various physiological processes including trimeric G proteins, which promotes the release of GDP IPN, Av. Instituto Politécnico cardiac function, immune responses, neurotransmission from the Gα subunit, followed by loading of GTP and dis- Nacional 2508, Col. San and sensory functions (such as vision, taste and olfac- sociation from Gβγ and from the receptor4. Then, GTP- Pedro Zacatenco, C.P. 07360, tion), but their aberrant activity or expression also con- bound Gα as well as Gβγ stimulate their cognate effectors México. 1 3Skaggs School of Pharmacy tributes to some of the most prevalent human diseases . as long as Gα remains loaded with GTP and the Gβγ and Pharmaceutical Sciences, Indeed, GPCRs are the direct or indirect target of more effector interface remains available for direct interactions University of California, than 25% of therapeutic drugs on the market2,3. with its effectors. Regulators of G protein signalling (RGS) San Diego, La Jolla, California GPCRs function as key transducers of signals from proteins turn off the switch represented by active Gα by 92093, USA. the extracellular milieu to the inside of the cell. Various promoting the GTPase activity of this subunit. Eventually, 4Department of Molecular Biology, Genentech Inc., entities, ranging from photons to lipids to small proteins, GDP-bound Gα re-associates with Gβγ, returning the 1 DNA Way, South San serve as ligands for different GPCRs, and all are capable of complex to an inactive state. The newly reassembled Francisco, California 94080, inducing conformational changes that promote receptor inactive hetero trimer can couple again with available USA. activation. Initial signal transduction is largely accom- agonist-stimulated GPCRs. This process is amplified and 5Department of Bioinformatics and plished by the receptor coupling to and activating hetero- regulated at its different signalling nodes, thus enforcing a Computational Biology, trimeric G proteins, which then mediate the activation of tight temporal and spatial control of GPCR signalling that Genentech Inc., 1 DNA Way, a number of second-messenger systems, small GTPases activates multiple targets depending on the specific G pro- South San Francisco, and an intricate network of kinase cascades. Ultimately, tein involved. Moreover, recent discoveries in GPCR biol- California 94080, USA. the activation of these GPCR-regulated signalling cir- ogy support the idea that receptors can exhibit different Correspondence to J.S.G. e-mail: [email protected] cuits can lead to changes in gene transcription, cell conformational states, which activate variable intracellular doi:10.1038/nrc3521 survival and motility, and normal and malignant signalling pathways and which are stabilized by different Published online 3 May 2013 cell growth. classes of ligands; ligand efficacy seems to be independent 412 | JUNE 2013 | VOLUME 13 www.nature.com/reviews/cancer © 2013 Macmillan Publishers Limited. All rights reserved ANALYSIS 8 G‑protein‑coupled receptors of affinity and varies between full agonists, partial ago- polarized division and proliferation . Gαi, in particular, (GPCRs). A family of receptor nists, inverse agonists and allosteric modulators. As such, is a component of the complex that determines the align- proteins that have seven-trans- GPCRs can be viewed as molecular rheostats rather than ment of the mitotic spindle with respect to the cellular membrane domains, an as simple on/off switches4. polarity axis of dividing stem or progenitor cells9. extracellular amino terminus and an intracellular carboxyl Different active conformations of GPCRs can stimu- Detailed three-dimensional structures of several terminus. They respond to late different G-protein-dependent and -independent GPCRs in various activation states have recently been stimuli outside the cell and pathways or elicit variable intensities of the downstream solved, adding to our understanding of GPCR structure transduce signals into the cells responses4. This dynamic range in receptor activity can and function. Established GPCR structures now include through interactions with be exploited therapeutically, enabling the use of biased or inactive and activated forms of rhodopsin, adrenergic and intracellular signalling proteins, including G proteins. allosteric modulators to selectively inhibit certain activi- adenosine receptors, as well as inactive conformations ties while preserving others. Furthermore, the activation of chemokine, dopamine, histamine and sphingosine G proteins of GPCRs is also influenced by their oligomerization state phosphate receptors and protease-activated receptor 1 A family of guanine-nucleotide- and subcellular localization, and their downstream effects (recently reviewed by Palczewski and colleagues10). The binding proteins that are 11 important for signal are expanded by the presence of recently recognized crystal structures of active adenosine A2A receptors transduction. Their activity is G-protein-independent pathways transduced via GPCR- and a quaternary complex of active agonist-occupied regulated by binding and interacting proteins, such as arrestins5. The G proteins β2-adrenergic receptor bound to nucleotide-free hetero- hydrolysing GTP such that the 12 themselves can be activated independently of GPCRs trimeric Gαs protein have also been published . In addi- active state is GTP-bound, by other mechanisms, including by receptor tyrosine tion, of particular interest for oncologists, the structure of whereas the inactive form is in a GDP-bound state. kinases, non-receptor guanine-nucleotide exchange factors the chemokine receptor CXCR4, which is a crucial regula- Heterotrimeric G proteins (GEFs) and other intracellular modulators that can tor of cell migration that is implicated in cancer metasta- consist of α-, β- and γ-subunits. elicit growth and proliferative properties6,7. For example, sis, has recently been revealed. This structure, visualized asymmetric cell division, which involves heterotrimeric at a resolution of 2.5 to 3.2 angstroms, is consistent with G proteins but is independent of GPCRs, can contrib- a constitutive homodimeric organization in which inter- ute to cancer progression owing to its role in stem cell acting residues in the fifth transmembrane (TM) α-helix (TM5) and TM6 form the dimeric interface13. Based on structural data, it seems that in the absence At a glance of their cognate agonists, many members of the fam- ily A GPCRs maintain an inactive conformation through • Recent cancer genome deep sequencing efforts have revealed an unanticipated high interactions between their TM3 and TM6 helices. In frequency of mutations in G proteins and G-protein-coupled receptors (GPCRs) in some GPCRs these TM helices are bridged intracellularly most tumour types. by polar interactions that are established between the • A striking 4.2% of all tumour sequences deposited to date show activating mutations in GNAS (a complex locus that encodes G ). Transforming mutations in GNAS have highly conserved E/DRY motif on TM3 and a glutamate αs 4,14 been well documented in human thyroid and pituitary tumours, and recent residue on TM6, forming what is called an ‘ionic lock’ . sequencing efforts have shown these mutations to be present in a wide variety of On ligand binding, transmembrane α-helices adjust their additional tumour types, including colon cancer, hepatocellular carcinoma, and position. TM6, in particular, moves outwards from the parathyroid, ovarian, endometrial, biliary tract and pancreatic tumours. centre of the bundle, loses contact with TM3 and moves • Mutually exclusive activating mutations in GNAQ or GNA11 (encoding
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