The G protein Gα_s acts as a tumor suppressor in sonic hedgehog signaling-driven tumorigenesis

References

• Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer 2007; 7:79-94; PMID:17251915; http://dx.doi.org/10.1038/nrc2069
   PubMed Web of Science ®Google Scholar
• Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br J Pharmacol 2009; 147:S46-S55; http://dx.doi.org/10.1038/sj.bjp.0706405
   Google Scholar
• Masuho I, Ostrovskaya O, Kramer GM, Jones CD, Xie K, Martemyanov KA. Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. Sci Signal 2015; 8:ra123-ra; PMID:26628681; http://dx.doi.org/10.1126/scisignal.aab4068
   PubMed Web of Science ®Google Scholar
• Yoda A, Adelmant G, Tamburini J, Chapuy B, Shindoh N, Yoda Y, Weigert O, Kopp N, Wu SC, Kim SS, et al. Mutations in G protein β subunits promote transformation and kinase inhibitor resistance. Nat Med 2015; 21:71-5; PMID:25485910; http://dx.doi.org/10.1038/nm.3751
   PubMed Web of Science ®Google Scholar
• Ward JD, Ha JH, Jayaraman M, Dhanasekaran DN. LPA-mediated migration of ovarian cancer cells involves translocalization of Gαi2 to invadopodia and association with Src and β-pix. Cancer Letters 2015; 356:382-91; PMID:25451317; http://dx.doi.org/10.1016/j.canlet.2014.09.030
   PubMed Web of Science ®Google Scholar
• Wang Z, Dela Cruz R, Ji F, Guo S, Zhang J, Wang Y, Feng GS, Birnbaumer L, Jiang M, Chu WM. G(i)α proteins exhibit functional differences in the activation of ERK1/2, Akt and mTORC1 by growth factors in normal and breast cancer cells. Cell Communication Signal 2014; 12:10; http://dx.doi.org/10.1186/1478-811X-12-10
   PubMed Web of Science ®Google Scholar
• Choi YJ, Kim SY, Oh JM, Juhnn YS. Stimulatory heterotrimeric G protein augments gamma ray-induced apoptosis by up-regulation of Bak expression via CREB and AP-1 in H1299 human lung cancer cells. Exp Mol Med 2009; 41:592-600; PMID:19381065; http://dx.doi.org/10.3858/emm.2009.41.8.065
   PubMed Web of Science ®Google Scholar
• Kumar KK, Burgess AW, Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci 2014; 23:551-65; PMID:24677446; http://dx.doi.org/10.1002/pro.2446
   PubMed Web of Science ®Google Scholar
• O'Hayre M, Degese MS, Gutkind JS. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol 2014; 27:126-35; PMID:24508914; http://dx.doi.org/10.1016/j.ceb.2014.01.005
   PubMed Web of Science ®Google Scholar
• Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 2010; 466:869-73; PMID:20668451; http://dx.doi.org/10.1038/nature09208
   PubMed Web of Science ®Google Scholar
• O'Hayre M, Vazquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S, Gutkind JS. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat Rev Cancer 2013; 13:412-24; PMID:23640210; http://dx.doi.org/10.1038/nrc3521
   PubMed Web of Science ®Google Scholar
• He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, Wang H, Deng Y, Yu Y, Xia Y, et al. The G protein α subunit Galphas is a tumor suppressor in Sonic hedgehog-driven medulloblastoma. Nat Med 2014; 20:1035-42; PMID:25150496; http://dx.doi.org/10.1038/nm.3666
   PubMed Web of Science ®Google Scholar
• Iglesias-Bartolome R, Torres D, Marone R, Feng X, Martin D, Simaan M, Chen M, Weinstein LS, Taylor SS, Molinolo AA, et al. Inactivation of a Gαs-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis. Nat Cell Biol 2015; 17(6):793-803:advance on; PMID:25961504; http://dx.doi.org/10.1038/ncb3164
   PubMed Web of Science ®Google Scholar
• Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, Zhao J, Yuan H, Tumaneng K, Li H, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 2012; 150:780-91; PMID:22863277; http://dx.doi.org/10.1016/j.cell.2012.06.037
   PubMed Web of Science ®Google Scholar
• Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, et al. Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition. Cancer Cell 2014; 25:393-405; PMID:24651015; http://dx.doi.org/10.1016/j.ccr.2014.02.004
   PubMed Web of Science ®Google Scholar
• Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012; 123:465-72; PMID:22134537; http://dx.doi.org/10.1007/s00401-011-0922-z
   PubMed Web of Science ®Google Scholar
• Huh JY, Kwon MJ, Seo KY, Kim MK, Chae KY, Kim SH, Ki CS, Yoon MS, Kim DH. Novel nonsense GNAS mutation in a 14-month-old boy with plate-like osteoma cutis and medulloblastoma. J Dermatol 2014; 41(4):319-21; PMID:24517547; http://dx.doi.org/10.1111/1346-8138.12284
   PubMed Web of Science ®Google Scholar
• Lupi O. Correlations between the Sonic Hedgehog pathway and basal cell carcinoma. Int J Dermatol 2007; 46:1113-7; PMID:17988327; http://dx.doi.org/10.1111/j.1365-4632.2007.03391.x
   PubMed Web of Science ®Google Scholar
• Decock A, Ongenaert M, Hoebeeck J, De Preter K, Van Peer G, Van Criekinge W, Ladenstein R, Schulte JH, Noguera R, Stallings RL, et al. Genome-wide promoter methylation analysis in neuroblastoma identifies prognostic methylation biomarkers. Genome Biol 2012; 13:R95-R; PMID:23034519; http://dx.doi.org/10.1186/gb-2012-13-10-r95
   PubMedGoogle Scholar
• Taylor SS, Zhang P, Steichen JM, Keshwani MM, Kornev AP. PKA: lessons learned after twenty years. Biochim Biophys Acta 2013; 1834:1271-8; PMID:23535202; http://dx.doi.org/10.1016/j.bbapap.2013.03.007
   PubMed Web of Science ®Google Scholar
• Stratakis CA. cAMP/PKA signaling defects in tumors: genetics and tissue-specific pluripotential cell-derived lesions in human and mouse. Mol Cell Endocrinol 2013; 371:208-20; PMID:23485729; http://dx.doi.org/10.1016/j.mce.2013.01.015
   PubMed Web of Science ®Google Scholar
• Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med 2013; 19:1410-22; PMID:24202394; http://dx.doi.org/10.1038/nm.3389
   PubMed Web of Science ®Google Scholar
• Chen Y, Jiang J. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res 2013; 23:186-200; PMID:23337587; http://dx.doi.org/10.1038/cr.2013.10
   PubMed Web of Science ®Google Scholar
• Ruiz i Altaba A, Mas C, Stecca B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 2007; 17:438-47; PMID:17845852; http://dx.doi.org/10.1016/j.tcb.2007.06.007
   PubMed Web of Science ®Google Scholar
• Nikulina E, Tidwell JL, Dai HN, Bregman BS, Filbin MT. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci U S A 2004; 101:8786-90; PMID:15173585; http://dx.doi.org/10.1073/pnas.0402595101
   PubMed Web of Science ®Google Scholar
• Conti M, Jin SL. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 1999; 63:1-38; PMID:10506827; http://dx.doi.org/10.1016/S0079-6603(08)60718-7
   PubMed Web of Science ®Google Scholar
• Makinodan M, Rosen KM, Ito S, Corfas G. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 2012; 337:1357-60; PMID:22984073; http://dx.doi.org/10.1126/science.1220845
   PubMed Web of Science ®Google Scholar
• Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009; 326:572-4; PMID:19726788; http://dx.doi.org/10.1126/science.1179386
   PubMed Web of Science ®Google Scholar
• Ng JM, Curran T. The Hedgehog's tale: developing strategies for targeting cancer. Nat Rev Cancer 2011; 11:493-501; PMID:21614026; http://dx.doi.org/10.1038/nrc3079
   PubMed Web of Science ®Google Scholar
• Nozawa YI, Lin C, Chuang PT. Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Curr Opin Genet Dev 2013; 23(4):429-37; PMID:23725801; http://dx.doi.org/10.1016/j.gde.2013.04.008
   PubMed Web of Science ®Google Scholar
• Goetz SC, Ocbina PJ, Anderson KV. The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol 2009; 94:199-222; PMID:20362092; http://dx.doi.org/10.1016/S0091-679X(08)94010-3
   PubMed Web of Science ®Google Scholar
• Pan Y, Wang C, Wang B. Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev Biol 2009; 326:177-89; PMID:19056373; http://dx.doi.org/10.1016/j.ydbio.2008.11.009
   PubMed Web of Science ®Google Scholar
• Tuson M, He M, Anderson KV. Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 2011; 138:4921-30; PMID:22007132; http://dx.doi.org/10.1242/dev.070805
   PubMed Web of Science ®Google Scholar
• Fernandez-L A, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev 2009; 23:2729-41; PMID:19952108; http://dx.doi.org/10.1101/gad.1824509
   PubMed Web of Science ®Google Scholar
• Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z, Zhao L, Peyman G, Ouyang H, Jiang W, et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 2014; 25:822-30; PMID:24882516; http://dx.doi.org/10.1016/j.ccr.2014.04.017
   PubMed Web of Science ®Google Scholar
• Riobo NA, Saucy B, Dilizio C, Manning DR. Activation of heterotrimeric G proteins by Smoothened. Proc Natl Acad Sci U S A 2006; 103:12607-12; PMID:16885213; http://dx.doi.org/10.1073/pnas.0600880103
   PubMed Web of Science ®Google Scholar
• Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ. G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature 2008; 456:967-70; PMID:18987629; http://dx.doi.org/10.1038/nature07459
   PubMed Web of Science ®Google Scholar
• Carbe CJ, Cheng L, Addya S, Gold JI, Gao E, Koch WJ, Riobo NA. Gi proteins mediate activation of the canonical hedgehog pathway in the myocardium. AJP: Heart Circulatory Physiol 2014; 307:H66-H72
   PubMed Web of Science ®Google Scholar
• Low WC, Wang C, Pan Y, Huang XY, Chen JK, Wang B. The decoupling of Smoothened from Galphai proteins has little effect on Gli3 protein processing and Hedgehog-regulated chick neural tube patterning. Dev Biol 2008; 321:188-96; PMID:18590719; http://dx.doi.org/10.1016/j.ydbio.2008.06.014
   PubMed Web of Science ®Google Scholar
• Philipp M, Caron MG. Hedgehog signaling: is Smo a G protein-coupled receptor? Curr Biol 2009; 19:R125-7; PMID:19211052; http://dx.doi.org/10.1016/j.cub.2008.12.010
   PubMedGoogle Scholar
• Polizio AH, Chinchilla P, Chen X, Kim S, Manning DR, Riobo NA. Heterotrimeric Gi proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J Biol Chem 2011; 286:19589-96; PMID:21474452; http://dx.doi.org/10.1074/jbc.M110.197111
   PubMed Web of Science ®Google Scholar
• Barzi M, Kostrz D, Menendez A, Pons S. Sonic Hedgehog-induced proliferation requires specific Gα inhibitory proteins. J Biol Chem 2011; 286:8067-74; PMID:21209076; http://dx.doi.org/10.1074/jbc.M110.178772
   PubMed Web of Science ®Google Scholar
• Singh J, Wen X, Scales SJ. The Orphan G Protein-Coupled Receptor Gpr175 (TPRA40) Enhances Hedgehog Signaling by Modulating cAMP Levels. J Biol Chem 2015:M115.665810-M115
   Google Scholar
• Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, Zaidi MR, Ksander BR, Merlino G, Sodhi A, et al. Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-Regulated Rho GTPase Signaling Circuitry. Cancer Cell 2014; 25:831-45; PMID:24882515; http://dx.doi.org/10.1016/j.ccr.2014.04.016
   PubMed Web of Science ®Google Scholar
• Whittier KL, Boese EA, Gibson-Corley KN, Kirby PA, Darbro BW, Qian Q, Ingram WJ, Robertson T, Remke M, Taylor MD, et al. G-protein coupled receptor expression patterns delineate medulloblastoma subgroups. Acta Neuropathologica Communications 2013; 1:66; PMID:24252460; http://dx.doi.org/10.1186/2051-5960-1-66
   PubMedGoogle Scholar
• Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, Jackson PK. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 2013; 152:210-23; PMID:23332756; http://dx.doi.org/10.1016/j.cell.2012.12.026
   PubMed Web of Science ®Google Scholar
• Niewiadomski P, Zhujiang A, Youssef M, Waschek JA. Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA. Cell Signal 2013; 25:2222-30; PMID:23872071; http://dx.doi.org/10.1016/j.cellsig.2013.07.012
   PubMed Web of Science ®Google Scholar
• Lelievre V, Seksenyan A, Nobuta H, Yong WH, Chhith S, Niewiadomski P, Cohen JR, Dong H, Flores A, Liau LM, et al. Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Dev Biol 2008; 313:359-70; PMID:18036580; http://dx.doi.org/10.1016/j.ydbio.2007.10.031
   PubMed Web of Science ®Google Scholar
• Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D, Rubin JB. Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res 2007; 67:651-8; PMID:17234775; http://dx.doi.org/10.1158/0008-5472.CAN-06-2762
   PubMed Web of Science ®Google Scholar
• Sengupta R, Dubuc A, Ward S, Yang L, Northcott P, Woerner BM, Kroll K, Luo J, Taylor MD, Wechsler-Reya RJ, et al. CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma. Cancer Res 2012; 72:122-32; PMID:22052462; http://dx.doi.org/10.1158/0008-5472.CAN-11-1701
   PubMed Web of Science ®Google Scholar
• Sengupta R, Sun T, Warrington NM, Rubin JB. Treating brain tumors with PDE4 inhibitors. Trends Pharmacol Sci 2011; 32:337-44; PMID:21450351; http://dx.doi.org/10.1016/j.tips.2011.02.015
   PubMed Web of Science ®Google Scholar
• Williams CH, Hempel JE, Hao J, Frist AY, Williams MM, Fleming JT, Sulikowski GA, Cooper MK, Chiang C, Hong CC. An In Vivo Chemical Genetic Screen Identifies Phosphodiesterase 4 as a Pharmacological Target for Hedgehog Signaling Inhibition. Cell Reports 2015; 11:43-50; PMID:25818300; http://dx.doi.org/10.1016/j.celrep.2015.03.001
   PubMed Web of Science ®Google Scholar
• Schmidt AL, de Farias CB, Abujamra AL, Kapczinski F, Schwartsmann G, Brunetto AL, Roesler R. BDNF and PDE4, but not the GRPR, regulate viability of human medulloblastoma cells. J Mol Neurosci 2010; 40:303-10; PMID:19642024; http://dx.doi.org/10.1007/s12031-009-9221-8
   PubMed Web of Science ®Google Scholar
• Ge X, Milenkovic L, Suyama K, Hartl T, Purzner T, Winans A, Meyer T, Scott MP. Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma. Elife 2015; 4:e07068; http://dx.doi.org/10.7554/eLife.07068
   Web of Science ®Google Scholar
• Goldhoff P, Warrington NM, Limbrick DD, Jr, Hope A, Woerner BM, Jackson E, Perry A, Piwnica-Worms D, Rubin JB. Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin Cancer Res 2008; 14:7717-25; PMID:19047098; http://dx.doi.org/10.1158/1078-0432.CCR-08-0827
   PubMed Web of Science ®Google Scholar
• Chahar MK, Sharma N, Dobhal MP, Joshi YC. Flavonoids: A versatile source of anticancer drugs. Pharmacogn Rev 2011; 5:1-12; PMID:22096313; http://dx.doi.org/10.4103/0973-7847.79093
   PubMedGoogle Scholar
• Nikaido T, Ohmoto T, Kinoshita T, Sankawa U, Delle Monache F, Botta B, Tomimori T, Miyaichi Y, Shirataki Y, Yokoe I, et al. Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by flavonoids. III. Chem Pharm Bull (Tokyo) 1989; 37:1392-5; PMID:2560949; http://dx.doi.org/10.1248/cpb.37.1392
   PubMed Web of Science ®Google Scholar
• Rodon J, Tawbi HA, Thomas AL, Stoller RG, Turtschi CP, Baselga J, Sarantopoulos J, Mahalingam D, Shou Y, Moles MA, et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res 2014; 20:1900-9; PMID:24523439; http://dx.doi.org/10.1158/1078-0432.CCR-13-1710
   PubMed Web of Science ®Google Scholar
• Kar S, Deb M, Sengupta D, Shilpi A, Bhutia SK, Patra SK. Intricacies of hedgehog signaling pathways: a perspective in tumorigenesis. Exp Cell Res 2012; 318:1959-72; PMID:22659135; http://dx.doi.org/10.1016/j.yexcr.2012.05.015
   PubMed Web of Science ®Google Scholar
• Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2010; 1805:181-208; PMID:20085802
   PubMed Web of Science ®Google Scholar