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Protein Interactomics by Two-Hybrid Methods

  • Soon Gang Choi
  • Aaron Richardson
  • Luke Lambourne
  • David E. Hill
  • Marc Vidal
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1794)

Abstract

Comprehensive identification of direct, physical interactions between biological macromolecules, such as protein–protein, protein–DNA, and protein–RNA interactions, is critical for our understanding of the function of gene products as well as the global organization and interworkings of various molecular machines within the cell. The accurate and comprehensive detection of direct interactions, however, remains a huge challenge due to the inherent structural complexity arising from various post-transcriptional and translational modifications coupled with huge heterogeneity in concentration, affinity, and subcellular location differences existing for any interacting molecules. This has created a need for developing multiple orthogonal and complementary assays for detecting various types of biological interactions. In this introduction, we discuss the methods developed for measuring different types of molecular interactions with an emphasis on direct protein–protein interactions, critical issues for generating high-quality interactome datasets, and the insights into biological networks and human diseases that current interaction mapping efforts provide. Further, we will discuss what future might lie ahead for the continued evolution of two-hybrid methods and the role of interactomics for expanding the advancement of biomedical science.

Key words

Interactome network Interactomics Systems biology Edgetics Protein-protein interaction Two-hybrid 

Notes

Acknowledgments

We thank Yang Wang, Hong Yue, Julien Olivet, and Michael Calderwood for critical reading of the manuscript and their valuable comments. This work was supported by a Claudia Adams Barr Program for Innovative Cancer Research Award to S.G.C., and NHGRI grants U41HG001715, awarded to D.E.H. and M.V., and P50HG004233, awarded to M.V. Soon Gang Choi and Aaron Richardson contributed equally to this work.

References

  1. 1.
    Venter JC (2010) Multiple personal genomes await. Nature 464(7289):676–677.  https://doi.org/10.1038/464676a CrossRefPubMedGoogle Scholar
  2. 2.
    Henson J, Tischler G, Ning Z (2012) Next-generation sequencing and large genome assemblies. Pharmacogenomics 13(8):901–915.  https://doi.org/10.2217/pgs.12.72 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Altshuler D, Daly MJ, Lander ES (2008) Genetic mapping in human disease. Science 322(5903):881–888.  https://doi.org/10.1126/science.1156409 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A (2015) OMIM.org: online mendelian inheritance in man (OMIM(R)), an online catalog of human genes and genetic disorders. Nucleic Acids Res 43(Database issue):D789–D798.  https://doi.org/10.1093/nar/gku1205 CrossRefPubMedGoogle Scholar
  5. 5.
    Vidal M, Cusick ME, Barabasi AL (2011) Interactome networks and human disease. Cell 144(6):986–998.  https://doi.org/10.1016/j.cell.2011.02.016 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, Yi S, Lemmens I, Fontanillo C, Mosca R, Kamburov A, Ghiassian SD, Yang X, Ghamsari L, Balcha D, Begg BE, Braun P, Brehme M, Broly MP, Carvunis A-R, Convery-Zupan D, Corominas R, Coulombe-Huntington J, Dann E, Dreze M, Dricot A, Fan C, Franzosa E, Gebreab F, Gutierrez BJ, Hardy MF, Jin M, Kang S, Kiros R, Lin GN, Luck K, MacWilliams A, Menche J, Murray RR, Palagi A, Poulin MM, Rambout X, Rasla J, Reichert P, Romero V, Ruyssinck E, Sahalie JM, Scholz A, Shah AA, Sharma A, Shen Y, Spirohn K, Tam S, Tejeda AO, Trigg SA, Twizere J-C, Vega K, Walsh J, Cusick ME, Xia Y, Barabási A-L, Iakoucheva LM, Aloy P, De Las Rivas J, Tavernier J, Calderwood MA, Hill DE, Hao T, Roth FP, Vidal M (2014) A proteome-scale map of the human interactome network. Cell 159(5):1212–1226.  https://doi.org/10.1016/j.cell.2014.10.050 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Zhong Q, Simonis N, Li QR, Charloteaux B, Heuze F, Klitgord N, Tam S, Yu H, Venkatesan K, Mou D, Swearingen V, Yildirim MA, Yan H, Dricot A, Szeto D, Lin C, Hao T, Fan C, Milstein S, Dupuy D, Brasseur R, Hill DE, Cusick ME, Vidal M (2009) Edgetic perturbation models of human inherited disorders. Mol Syst Biol 5:321.  https://doi.org/10.1038/msb.2009.80 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Fields S, Song O (1989) A novel genetic system to detect protein-protein interactions. Nature 340(6230):245–246.  https://doi.org/10.1038/340245a0 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wiemann SPC, Hu Y, Hunter P, Harbers M, Amiet A, Bethel G, Busse M, Carninci P, Dunham I, Hao T, Harper JW, Hayashizaki Y, Heil O, Hennig S, Hotz-Wagenblatt A, Jang W, Jöcker A, Kawai J, Koenig C, Korn B, Lambert C, LeBeau A, Lu S, Maurer J, Moore T, Ohara O, Park J, Rolfs A, Salehi-Ashtiani K, Seiler C, Simmons B, van Brabant Smith A, Steel J, Wagner L, Weaver T, Wellenreuther R, Yang S, Vidal M, Gerhard DS, LaBaer J, Temple G, Hill DE (2016) The ORFeome collaboration: a genome-scale human ORF-clone resource. Nat Methods 13(3):191–192.  https://doi.org/10.1038/nmeth.3776 CrossRefGoogle Scholar
  10. 10.
    Vidal M, Brachmann RK, Fattaey A, Harlow E, Boeke JD (1996) Reverse two-hybrid and one-hybrid systems to detect dissociation of protein-protein and DNA-protein interactions. Proc Natl Acad Sci U S A 93(19):10315–10320CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Johnsson N, Varshavsky A (1994) Split ubiquitin as a sensor of protein interactions in vivo. Proc Natl Acad Sci U S A 91(22):10340–10344CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Thaminy S, Miller J, Stagljar I (2004) The split-ubiquitin membrane-based yeast two-hybrid system. Methods Mol Biol 261:297–312.  https://doi.org/10.1385/1-59259-762-9:297 CrossRefPubMedGoogle Scholar
  13. 13.
    Ear PH, Kowarzyk J, Booth MJ, Abd-Rabbo D, Shulist K, Hall C, Vogel J, Michnick SW (2016) Combining the optimized yeast cytosine deaminase protein fragment complementation assay and an in vitro Cdk1 targeting assay to study the regulation of the gamma-tubulin complex. Methods Mol Biol 1342:237–257.  https://doi.org/10.1007/978-1-4939-2957-3_14 CrossRefPubMedGoogle Scholar
  14. 14.
    Remy I, Campbell-Valois FX, Michnick SW (2007) Detection of protein-protein interactions using a simple survival protein-fragment complementation assay based on the enzyme dihydrofolate reductase. Nat Protoc 2(9):2120–2125.  https://doi.org/10.1038/nprot.2007.266 CrossRefPubMedGoogle Scholar
  15. 15.
    Cassonnet P, Rolloy C, Neveu G, Vidalain PO, Chantier T, Pellet J, Jones L, Muller M, Demeret C, Gaud G, Vuillier F, Lotteau V, Tangy F, Favre M, Jacob Y (2011) Benchmarking a luciferase complementation assay for detecting protein complexes. Nat Methods 8(12):990–992.  https://doi.org/10.1038/nmeth.1773 CrossRefPubMedGoogle Scholar
  16. 16.
    Ozawa T, Kaihara A, Sato M, Tachihara K, Umezawa Y (2001) Split luciferase as an optical probe for detecting protein-protein interactions in mammalian cells based on protein splicing. Anal Chem 73(11):2516–2521CrossRefPubMedGoogle Scholar
  17. 17.
    Paulmurugan R, Gambhir SS (2003) Monitoring protein-protein interactions using split synthetic renilla luciferase protein-fragment-assisted complementation. Anal Chem 75(7):1584–1589CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hu CD, Chinenov Y, Kerppola TK (2002) Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell 9(4):789–798CrossRefPubMedGoogle Scholar
  19. 19.
    Eyckerman S, Verhee A, der Heyden JV, Lemmens I, Ostade XV, Vandekerckhove J, Tavernier J (2001) Design and application of a cytokine-receptor-based interaction trap. Nat Cell Biol 3(12):1114–1119.  https://doi.org/10.1038/ncb1201-1114 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lievens S, Gerlo S, Lemmens I, De Clercq DJ, Risseeuw MD, Vanderroost N, De Smet AS, Ruyssinck E, Chevet E, Van Calenbergh S, Tavernier J (2014) Kinase substrate sensor (KISS), a mammalian in situ protein interaction sensor. Mol Cell Proteomics 13(12):3332–3342.  https://doi.org/10.1074/mcp.M114.041087 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Aronheim A (2004) Ras signaling pathway for analysis of protein-protein interactions in yeast and mammalian cells. Methods Mol Biol 250:251–262.  https://doi.org/10.1385/1-59259-671-1:251 CrossRefPubMedGoogle Scholar
  22. 22.
    Karimova G, Gauliard E, Davi M, Ouellette SP, Ladant D (2017) Protein-protein interaction: bacterial two-hybrid. Methods Mol Biol 1615:159–176.  https://doi.org/10.1007/978-1-4939-7033-9_13 CrossRefPubMedGoogle Scholar
  23. 23.
    Karimova G, Ullmann A, Ladant D (2001) Protein-protein interaction between Bacillus stearothermophilus tyrosyl-tRNA synthetase subdomains revealed by a bacterial two-hybrid system. J Mol Microbiol Biotechnol 3(1):73–82PubMedPubMedCentralGoogle Scholar
  24. 24.
    Fuxman Bass JI, Reece-Hoyes JS, Walhout AJ (2016) Gene-centered yeast one-hybrid assays. Cold Spring Harb Protoc 2016(12):top077669.  https://doi.org/10.1101/pdb.top077669 CrossRefGoogle Scholar
  25. 25.
    SenGupta DJ, Zhang B, Kraemer B, Pochart P, Fields S, Wickens M (1996) A three-hybrid system to detect RNA-protein interactions in vivo. Proc Natl Acad Sci U S A 93(16):8496–8501CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Cho SK, Kang IH, Carr T, Hannapel DJ (2012) Using the yeast three-hybrid system to identify proteins that interact with a phloem-mobile mRNA. Front Plant Sci 3:189.  https://doi.org/10.3389/fpls.2012.00189 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang Y, Letham DS, John PC, Zhang R (2016) Synthesis of a cytokinin linked by a spacer to dexamethasone and biotin: conjugates to detect cytokinin-binding proteins. Molecules 21(5).  https://doi.org/10.3390/molecules21050576 CrossRefGoogle Scholar
  28. 28.
    Licitra EJ, Liu JO (1996) A three-hybrid system for detecting small ligand-protein receptor interactions. Proc Natl Acad Sci U S A 93(23):12817–12821CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Becker F, Murthi K, Smith C, Come J, Costa-Roldan N, Kaufmann C, Hanke U, Degenhart C, Baumann S, Wallner W, Huber A, Dedier S, Dill S, Kinsman D, Hediger M, Bockovich N, Meier-Ewert S, Kluge AF, Kley N (2004) A three-hybrid approach to scanning the proteome for targets of small molecule kinase inhibitors. Chem Biol 11(2):211–223.  https://doi.org/10.1016/j.chembiol.2004.02.001 CrossRefPubMedGoogle Scholar
  30. 30.
    Cottier S, Monig T, Wang Z, Svoboda J, Boland W, Kaiser M, Kombrink E (2011) The yeast three-hybrid system as an experimental platform to identify proteins interacting with small signaling molecules in plant cells: potential and limitations. Front Plant Sci 2:101.  https://doi.org/10.3389/fpls.2011.00101 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Venkatesan K, Rual J-F, Vazquez A, Stelzl U, Lemmens I, Hirozane-Kishikawa T, Hao T, Zenkner M, Xin X, Goh KI, Yildirim MA, Simonis N, Heinzmann K, Gebreab F, Sahalie JM, Cevik S, Simon C, de Smet AS, Dann E, Smolyar A, Vinayagam A, Yu H, Szeto D, Borick H, Dricot A, Klitgord N, Murray RR, Lin C, Lalowski M, Timm J, Rau K, Boone C, Braun P, Cusick ME, Roth FP, Hill DE, Tavernier J, Wanker EE, Barabási A-L, Vidal M (2009) An empirical framework for binary interactome mapping. Nat Methods 6(1):83–90.  https://doi.org/10.1038/nmeth.1280 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Braun P, Taşan M, Dreze M, Barrios-Rodiles M, Lemmens I, Yu H, Sahalie JM, Murray RR, Roncari L, de Smet AS, Venkatesan K, Rual J-F, Vandenhaute J, Cusick ME, Pawson T, Hill DE, Tavernier J, Wrana JL, Roth FP, Vidal M (2009) An experimentally derived confidence score for binary protein-protein interactions. Nat Methods 6(1):91–97.  https://doi.org/10.1038/nmeth.1281 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL (2007) The human disease network. Proc Natl Acad Sci U S A 104(21):8685–8690.  https://doi.org/10.1073/pnas.0701361104 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Feldman I, Rzhetsky A, Vitkup D (2008) Network properties of genes harboring inherited disease mutations. Proc Natl Acad Sci U S A 105(11):4323–4328.  https://doi.org/10.1073/pnas.0701722105 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Barabasi AL, Gulbahce N, Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12(1):56–68.  https://doi.org/10.1038/nrg2918 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ghiassian SD, Menche J, Barabasi AL (2015) A DIseAse MOdule detection (DIAMOnD) algorithm derived from a systematic analysis of connectivity patterns of disease proteins in the human interactome. PLoS Comput Biol 11(4):e1004120.  https://doi.org/10.1371/journal.pcbi.1004120 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhou X, Menche J, Barabasi AL, Sharma A (2014) Human symptoms-disease network. Nat Commun 5:4212.  https://doi.org/10.1038/ncomms5212 CrossRefPubMedGoogle Scholar
  38. 38.
    Menche J, Sharma A, Kitsak M, Ghiassian SD, Vidal M, Loscalzo J, Barabasi AL (2015) Disease networks. Uncovering disease-disease relationships through the incomplete interactome. Science 347(6224):1257601.  https://doi.org/10.1126/science.1257601 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabasi AL, Vidal M, Zoghbi HY (2006) A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125(4):801–814.  https://doi.org/10.1016/j.cell.2006.03.032 CrossRefPubMedGoogle Scholar
  40. 40.
    Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, Rennert G, Moreno V, Kirchhoff T, Gold B, Assmann V, Elshamy WM, Rual JF, Levine D, Rozek LS, Gelman RS, Gunsalus KC, Greenberg RA, Sobhian B, Bertin N, Venkatesan K, Ayivi-Guedehoussou N, Sole X, Hernandez P, Lazaro C, Nathanson KL, Weber BL, Cusick ME, Hill DE, Offit K, Livingston DM, Gruber SB, Parvin JD, Vidal M (2007) Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet 39(11):1338–1349.  https://doi.org/10.1038/ng.2007.2 CrossRefPubMedGoogle Scholar
  41. 41.
    Luck K, Sheynkman GM, Zhang I, Vidal M (2017) Proteome-scale human interactomics. Trends Biochem Sci 42(5):342–354.  https://doi.org/10.1016/j.tibs.2017.02.006 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rozenblatt-Rosen O, Deo RC, Padi M, Adelmant G, Calderwood MA, Rolland T, Grace M, Dricot A, Askenazi M, Tavares M, Pevzner SJ, Abderazzaq F, Byrdsong D, Carvunis AR, Chen AA, Cheng J, Correll M, Duarte M, Fan C, Feltkamp MC, Ficarro SB, Franchi R, Garg BK, Gulbahce N, Hao T, Holthaus AM, James R, Korkhin A, Litovchick L, Mar JC, Pak TR, Rabello S, Rubio R, Shen Y, Singh S, Spangle JM, Tasan M, Wanamaker S, Webber JT, Roecklein-Canfield J, Johannsen E, Barabasi AL, Beroukhim R, Kieff E, Cusick ME, Hill DE, Munger K, Marto JA, Quackenbush J, Roth FP, DeCaprio JA, Vidal M (2012) Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 487(7408):491–495.  https://doi.org/10.1038/nature11288 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526(7571):68–74.  https://doi.org/10.1038/nature15393 CrossRefGoogle Scholar
  44. 44.
    Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN (2012) The human gene mutation database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics Chapter 1:Unit1 13. doi: https://doi.org/10.1002/0471250953.bi0113s39
  45. 45.
    Wang X, Wei X, Thijssen B, Das J, Lipkin SM, Yu H (2012) Three-dimensional reconstruction of protein networks provides insight into human genetic disease. Nat Biotechnol 30(2):159–164.  https://doi.org/10.1038/nbt.2106 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Zhong Q, Simonis N, Li QR, Charloteaux B, Heuze F, Klitgord N, Tam S, Yu HY, Venkatesan K, Mou D, Swearingen V, Yildirim MA, Yan H, Dricot A, Szeto D, Lin CW, Hao T, Fan CY, Milstein S, Dupuy D, Brasseur R, Hill DE, Cusick ME, Vidal M (2009) Edgetic perturbation models of human inherited disorders. Mol Syst Biol 5:10.  https://doi.org/10.1038/msb.2009.80 CrossRefGoogle Scholar
  47. 47.
    Sahni N, Yi S, Taipale M, Bass JIF, Coulombe-Huntington J, Yang F, Peng J, Weile J, Karras GI, Wang Y, Kovacs IA, Kamburov A, Krykbaeva I, Lam MH, Tucker G, Khurana V, Sharma A, Liu YY, Yachie N, Zhong Q, Shen Y, Palagi A, San-Miguel A, Fan CY, Balcha D, Dricot A, Jordan DM, Walsh JM, Shah AA, Yang XP, Stoyanova AK, Leighton A, Calderwood MA, Jacob Y, Cusick ME, Salehi-Ashtiani K, Whitesell LJ, Sunyaev S, Berger B, Barabási A-L, Charloteaux B, Hill DE, Hao T, Roth FP, Xia Y, Walhout AJM, Lindquist S, Vidal M (2015) Widespread macromolecular interaction perturbations in human genetic disorders. Cell 161(3):647–660.  https://doi.org/10.1016/j.cell.2015.04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Krogan NJ, Lippman S, Agard DA, Ashworth A, Ideker T (2015) The cancer cell map initiative: defining the hallmark networks of cancer. Mol Cell 58(4):690–698.  https://doi.org/10.1016/j.molcel.2015.05.008 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Engin HB, Kreisberg JF, Carter H (2016) Structure-based analysis reveals cancer missense mutations target protein interaction interfaces. PLoS One 11(4):e0152929.  https://doi.org/10.1371/journal.pone.0152929 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hosp F, Vossfeldt H, Heinig M, Vasiljevic D, Arumughan A, Wyler E, Landthaler M, Hubner N, Wanker EE, Lannfelt L, Ingelsson M, Lalowski M, Voigt A, Selbach M, Genetic, Environmental Risk for Alzheimer's Disease GC (2015) Quantitative interaction proteomics of neurodegenerative disease proteins. Cell Rep 11(7):1134–1146.  https://doi.org/10.1016/j.celrep.2015.04.030 CrossRefPubMedGoogle Scholar
  51. 51.
    Grefen C, Obrdlik P, Harter K (2009) The determination of protein-protein interactions by the mating-based split-ubiquitin system (mbSUS). Methods Mol Biol 479:217–233.  https://doi.org/10.1007/978-1-59745-289-2_14 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yachie N, Petsalaki E, Mellor JC, Weile J, Jacob Y, Verby M, Ozturk SB, Li S, Cote AG, Mosca R, Knapp JJ, Ko M, Yu A, Gebbia M, Sahni N, Yi S, Tyagi T, Sheykhkarimli D, Roth JF, Wong C, Musa L, Snider J, Liu YC, Yu H, Braun P, Stagljar I, Hao T, Calderwood MA, Pelletier L, Aloy P, Hill DE, Vidal M, Roth FP (2016) Pooled-matrix protein interaction screens using barcode fusion genetics. Mol Syst Biol 12(4):863.  https://doi.org/10.15252/msb.20156660 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Gu L, Li C, Aach J, Hill DE, Vidal M, Church GM (2014) Multiplex single-molecule interaction profiling of DNA-barcoded proteins. Nature 515(7528):554–557.  https://doi.org/10.1038/nature13761 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Trigg SA, Garza RM, MacWilliams A, Nery JR, Bartlett A, Castanon R, Goubil A, Feeney J, O'Malley R, Huang SC, Zhang ZZ, Galli M, Ecker JR (2017) CrY2H-seq: a massively multiplexed assay for deep-coverage interactome mapping. Nat Methods 14(8):819–825.  https://doi.org/10.1038/nmeth.4343 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wang Y, Sahni N, Vidal M (2015) Global edgetic rewiring in cancer networks. Cell Syst 1(4):251–253.  https://doi.org/10.1016/j.cels.2015.10.006 CrossRefPubMedGoogle Scholar
  56. 56.
    Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov 15(8):533–550.  https://doi.org/10.1038/nrd.2016.29 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Soon Gang Choi
    • 1
    • 2
    • 3
  • Aaron Richardson
    • 1
    • 2
    • 3
  • Luke Lambourne
    • 1
    • 2
    • 3
  • David E. Hill
    • 1
    • 2
    • 3
  • Marc Vidal
    • 1
    • 3
  1. 1.Center for Cancer Systems Biology (CCSB)Dana-Farber Cancer InstituteBostonUSA
  2. 2.Department of Cancer BiologyDana-Farber Cancer InstituteBostonUSA
  3. 3.Department of GeneticsHarvard Medical SchoolBostonUSA

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