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Perspective

The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block

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Pages 607-612 | Received 21 Nov 2016, Accepted 10 Jan 2017, Published online: 13 Mar 2017

References

  • Dror RO, Mildorf TJ, Hilger D, Manglik A, Borhani DW, Arlow DH, Philippsen A, Villanueva N, Yang Z, Lerch MT, et al. SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins. Science 2015; 348:1361-1365; PMID:26089515; http://dx.doi.org/10.1126/science.aaa5264
  • Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, et al. Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 2011; 477:549-555; PMID:21772288; http://dx.doi.org/10.1038/nature10361
  • Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, et al. Structure and function of an irreversible agonist-beta(2) adrenoceptor complex. Nature 2011; 469:236-240; PMID:21228876; http://dx.doi.org/10.1038/nature09665
  • Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, et al. Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor. Nature 2011; 469:175-180; PMID:21228869; http://dx.doi.org/10.1038/nature09648
  • Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov 2002; 1:727-730; PMID:12209152; http://dx.doi.org/10.1038/nrd892
  • Siderovski DP, Willard FS. The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci 2005; 1:51-66; PMID:15951850; http://dx.doi.org/10.7150/ijbs.1.51
  • Sato M, Blumer JB, Simon V, Lanier SM. Accessory proteins for G proteins: partners in signaling. Annu Rev Pharmacol Toxicol 2006; 46:151-187; PMID:16402902; http://dx.doi.org/10.1146/annurev.pharmtox.46.120604.141115
  • Siderovski DP, Willard FS. The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci 2005; 1:51-66; http://dx.doi.org/10.7150/ijbs.1.51
  • Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 2000; 69:795-827; PMID:10966476; http://dx.doi.org/10.1146/annurev.biochem.69.1.795
  • Blumer JB, Oner SS, Lanier SM. Group II activators of G-protein signalling and proteins containing a G-protein regulatory motif. Acta Physiol (Oxf) 2012; 204:202-218; PMID:21615707; http://dx.doi.org/10.1111/j.1748-1716.2011.02327.x
  • De Vries L, Zheng B, Fischer T, Elenko E, Farquhar MG. The regulator of G protein signaling family. Annu Rev Pharmacol Toxicol 2000; 40:235-271; PMID:10836135; http://dx.doi.org/10.1146/annurev.pharmtox.40.1.235
  • Sjogren B. Regulator of G protein signaling proteins as drug targets: current state and future possibilities. Adv Pharmacol 2011; 62:315-347; PMID:21907914
  • Appleton KM, Bigham KJ, Lindsey CC, Hazard S, Lirjoni J, Parnham S, Hennig M, Peterson YK. Development of inhibitors of heterotrimeric Galphai subunits. Bioorg Med Chem 2014; 22:3423-3434; PMID:24818958; http://dx.doi.org/10.1016/j.bmc.2014.04.035
  • Aznar N, Kalogriopoulos N, Midde KK, Ghosh P. Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time. Bioessays 2016; 38:379-393; PMID:26879989; http://dx.doi.org/10.1002/bies.201500133
  • Gupta V, Bhandari D, Leyme A, Aznar N, Midde KK, Lo IC, Ear J, Niesman I, Lopez-Sanchez I, Blanco-Canosa JB, et al. GIV/Girdin activates Galphai and inhibits Galphas via the same motif. Proc Natl Acad Sci U S A 2016; 113:E5721-5730; PMID:27621449; http://dx.doi.org/10.1073/pnas.1609502113
  • Yankelowitz BY. Biology, blind men, and elephants. Br Med J 1978; 2:1775; PMID:20792776; http://dx.doi.org/10.1136/bmj.2.6154.1775
  • Le-Niculescu H, Niesman I, Fischer T, DeVries L, Farquhar MG. Identification and characterization of GIV, a novel Galpha i/s-interacting protein found on COPI, endoplasmic reticulum-Golgi transport vesicles. J Biol Chem 2005; 280:22012-22020; PMID:15749703; http://dx.doi.org/10.1074/jbc.M501833200
  • Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y, Ono H, Fujishiro M, Fukushima Y, Horike N, et al. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem 2005; 280:18525-18535; PMID:15753085; http://dx.doi.org/10.1074/jbc.M500586200
  • Simpson F, Martin S, Evans TM, Kerr M, James DE, Parton RG, Teasdale RD. Wicking CA novel hook-related protein family and the characterization of hook-related protein 1. Traffic 2005; 6:442-458; PMID:15882442; http://dx.doi.org/10.1111/j.1600-0854.2005.00289.x
  • Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 2005; 9:389-402; PMID:16139227; http://dx.doi.org/10.1016/j.devcel.2005.08.001
  • Ghosh P, Garcia-Marcos M, Bornheimer SJ, Farquhar MG. Activation of Galphai3 triggers cell migration via regulation of GIV. J Cell Biol 2008; 182:381-393; PMID:18663145; http://dx.doi.org/10.1083/jcb.200712066
  • Johnston CA, Willard FS, Jezyk MR, Fredericks Z, Bodor ET, Jones MB, Blaesius R, Watts VJ, Harden TK, Sondek J, et al. Structure of Galpha(i1) bound to a GDP-selective peptide provides insight into guanine nucleotide exchange. Structure 2005; 13:1069-1080; PMID:16004878; http://dx.doi.org/10.1016/j.str.2005.04.007
  • Johnston CA, Ramer JK, Blaesius R, Fredericks Z, Watts VJ, Siderovski DP. A bifunctional Galphai/Galphas modulatory peptide that attenuates adenylyl cyclase activity. FEBS Lett 2005; 579:5746-5750; PMID:16225870; http://dx.doi.org/10.1016/j.febslet.2005.09.059
  • Garcia-Marcos M, Kietrsunthorn PS, Wang H, Ghosh PM, Farquhar MG. G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs. J Biol Chem 2011; 286:28138-28149; PMID:21653697; http://dx.doi.org/10.1074/jbc.M110.204099
  • Aznar N, Midde KK, Dunkel Y, Lopez-Sanchez I, Pavlova Y, Marivin A, Barbazan J, Murray F, Nitsche U, Janssen KP, et al. Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. Elife 2015; 4:e07091; PMID:26126266; http://dx.doi.org/10.7554/eLife.07091
  • Garcia-Marcos M, Ghosh P, Farquhar MG. GIV is a nonreceptor GEF for G alpha i with a unique motif that regulates Akt signaling. Proc Natl Acad Sci U S A 2009; 106:3178-3183; PMID:19211784; http://dx.doi.org/10.1073/pnas.0900294106
  • Garcia-Marcos M, Ear J, Farquhar MG, Ghosh P. A GDI (AGS3) and a GEF (GIV) regulate autophagy by balancing G protein activity and growth factor signals. Mol Biol Cell 2011; 22:673-686; PMID:21209316; http://dx.doi.org/10.1091/mbc.E10-08-0738
  • Garcia-Marcos M, Ghosh P, Ear J, Farquhar MG. A structural determinant that renders G alpha(i) sensitive to activation by GIV/girdin is required to promote cell migration. J Biol Chem 2010; 285:12765-12777; PMID:20157114; http://dx.doi.org/10.1074/jbc.M109.045161
  • Coleman DE, Berghuis AM, Lee E, Linder ME, Gilman AG¸Sprang SR. Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. Science (New York, N.Y) 1994; 265:1405-1412; PMID:8073283; http://dx.doi.org/10.1126/science.8073283
  • Aznar N, Kalogriopoulos N, Midde K, Lo IC¸Ghosh P. Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space and time. BioEssays 2016; 38(4):379-93; PMID:26879989
  • Ghosh P, Beas AO, Bornheimer SJ, Garcia-Marcos M, Forry EP, Johannson C, Ear J, Jung BH, Cabrera B, Carethers JM, et al. A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Mol Biol Cell 2010; 21:2338-2354; PMID:20462955; http://dx.doi.org/10.1091/mbc.E10-01-0028
  • Tsvetanova NG, Irannejad R, von Zastrow M. G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins from endosomes. J Biol Chem 2015; 290:6689-6696; PMID:25605726; http://dx.doi.org/10.1074/jbc.R114.617951
  • Irannejad R, von Zastrow M. GPCR signaling along the endocytic pathway. Curr Opin Cell Biol 2014; 27:109-116; PMID:24680436; http://dx.doi.org/10.1016/j.ceb.2013.10.003
  • Irannejad R, Tomshine JC, Tomshine JR, Chevalier M, Mahoney JP, Steyaert J, Rasmussen SG, Sunahara RK, El-Samad H, Huang B, et al. Conformational biosensors reveal GPCR signalling from endosomes. Nature 2013; 495:534-538; PMID:23515162; http://dx.doi.org/10.1038/nature12000
  • Bhandari D, Lopez-Sanchez I, To A, Lo IC, Aznar N, Leyme A, Gupta V, Niesman I, Maddox AL, Garcia-Marcos M, et al. Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration-proliferation dichotomy. Proc Natl Acad Sci U S A 2015; 112:E4874-4883; PMID:26286990; http://dx.doi.org/10.1073/pnas.1514157112
  • Lopez-Sanchez I, Garcia-Marcos M, Mittal Y, Aznar N, Farquhar MG, Ghosh P. Protein kinase C-theta (PKCtheta) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin. Proc Natl Acad Sci U S A 2013; 110:5510-5515; PMID:23509302; http://dx.doi.org/10.1073/pnas.1303392110
  • Coleman BD, Marivin A, Parag-Sharma K, DiGiacomo V, Kim S, Pepper JS, Casler J, Nguyen LT, Koelle MR, Garcia-Marcos M. Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation. Mol Biol Evol 2016; 33:820-837; PMID:26659249; http://dx.doi.org/10.1093/molbev/msv336
  • Zaccolo M. Spatial control of cAMP signalling in health and disease. Curr Opin Pharmacol 2011; 11:649-655; PMID:22000603; http://dx.doi.org/10.1016/j.coph.2011.09.014
  • Bonacci TM, Mathews JL, Yuan C, Lehmann DM, Malik S, Wu D, Font JL, Bidlack JM, Smrcka AV. Differential targeting of Gbetagamma-subunit signaling with small molecules. Science 2006; 312:443-446; PMID:16627746; http://dx.doi.org/10.1126/science.1120378
  • Dupre DJ, Robitaille M, Rebois RV, Hebert TE. The role of Gbetagamma subunits in the organization, assembly, and function of GPCR signaling complexes. Annu Rev Pharmacol Toxicol 2009; 49:31-56; PMID:18834311; http://dx.doi.org/10.1146/annurev-pharmtox-061008-103038
  • Azeloglu EU, Iyengar R. Signaling networks: information flow, computation, and decision making. Cold Spring Harb Perspect Biol 2015; 7:a005934; PMID:25833842; http://dx.doi.org/10.1101/cshperspect.a005934
  • Ma'ayan A, Iyengar R. From components to regulatory motifs in signalling networks. Brief Funct Genomic Proteomic 2006; 5:57-61; PMID:16769680; http://dx.doi.org/10.1093/bfgp/ell004

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