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An international journal for chemical science
RESEARCH ARTICLE

On the development of proteomics: a brief history

Ralph A. Bradshaw https://orcid.org/0000-0003-4972-9145 A *
+ Author Affiliations
- Author Affiliations

A Department of Physiology & Biophysics, University of California, Irvine, CA, USA.

* Correspondence to: rablab@uci.edu

Handling Editor: John Wade

Australian Journal of Chemistry 76(8) 418-428 https://doi.org/10.1071/CH23012
Submitted: 18 January 2023  Accepted: 10 February 2023   Published: 4 May 2023

© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing.

Abstract

Although one can trace the roots of proteomics well back into the 20th century, it is basically a discipline of the new millennium. At its outset, it was defined primarily by the technology available to analyze complex mixtures (basically 2D-gel electrophoresis, hybridizations/arrays and mass spectrometry) and what mainly set it aside from protein chemistry, that had flourished since the end of the second world war, was this use of unfractionated starting material as opposed to homogenous samples. Early on, two major new insights were quickly revealed: that the protein complement of cells was overwhelmingly involved in multiple protein–protein interactions and that it was nearly universally involved in a myriad of post-translational modifications. The revelations of the complex networks that result from these two phenomena have created a new understanding of cell biology that has affected our appreciation of such processes as transcription and translation, transmembrane signaling, differentiation, homeostasis and cell death. The development of these methods and strategies that principally characterize the field of proteomics depended heavily on the evolution of those that advanced protein chemistry, particularly during the last half of the twentieth century leading up to the elucidation of the human genome and will be briefly summarized in this article.

Keywords: 2D electrophoresis, 2D NMR, amino acid sequence, chromatography, crystallography, genomics, hybridizations/arrays, mass spectrometry, post‐translational modifications, protein–protein interactions, proteomics.


References

[1]  VC Wasinger, SJ Cordwell, A Cerpa-Poljak, JX Yan, AA Gooley, MR Wilkins, MW Duncan, R Harris, KL Williams, I Humphery-Smith, Progress with gene-product mapping of the Mollicutes: Mycoplasma genitalium. Electrophoresis 1995, 16, 1090.
         | Progress with gene-product mapping of the Mollicutes: Mycoplasma genitalium.Crossref | GoogleScholarGoogle Scholar |

[2]  CM Fraser, JD Gocayne, O White, MD Adams, RA Clayton, RD Fleischmann, CJ Bult, AR Kerlavage, G Sutton, JM Kelley, JL Fritchman, JF Weidman, KV Small, M Sandusky, J Fuhrmann, D Nguyen, TR Utterback, DM Saudek, CA Phillips, JM Merrick, J-F Tomb, BA Dougherty, KF Bott, P-C Hu, TS Lucier, SN Peterson, HO Smith, CA Hutchison III, JC Venter, The minimal gene complement of Mycoplasma genitalium. Science 1995, 270, 397.
         | The minimal gene complement of Mycoplasma genitalium.Crossref | GoogleScholarGoogle Scholar |

[3]  PH O’Farrell, High resolution two-dimensional electrophoresis of proteins. J Biol Chem 1975, 250, 4007.
         | High resolution two-dimensional electrophoresis of proteins.Crossref | GoogleScholarGoogle Scholar |

[4]  J Klose, Protein mapping by combined isoelectric focusing and electrophoresis of mouse tissues. Humangenetik 1975, 26, 231.
         | Protein mapping by combined isoelectric focusing and electrophoresis of mouse tissues.Crossref | GoogleScholarGoogle Scholar |

[5]  S Fields, R Sternglanz, The two-hybrid system: an assay for protein-protein interactions. Trends Genet 1994, 10, 286.
         | The two-hybrid system: an assay for protein-protein interactions.Crossref | GoogleScholarGoogle Scholar |

[6]  T-W Chang, Binding of cells to matrixes of distinct antibodies coated on solid surface. J Immunol Methods 1983, 65, 217.
         | Binding of cells to matrixes of distinct antibodies coated on solid surface.Crossref | GoogleScholarGoogle Scholar |

[7]  M Karas, D Bachmann, F Hillenkamp, Influence of the wavelength in high-irradiance ultraviolet laser desorption mass spectrometry of organic molecules. Anal Chem 1985, 57, 2935.
         | Influence of the wavelength in high-irradiance ultraviolet laser desorption mass spectrometry of organic molecules.Crossref | GoogleScholarGoogle Scholar |

[8]  K Tanaka, H Waki, Y Ido, S Akita, Y Yoshida, T Yoshida, T Matsuo, Protein and polymer analyses up to m/z 100 000 by laser ionization time-of flight mass spectrometry. Rapid Commun Mass Spectrom 1988, 2, 151.
         | Protein and polymer analyses up to m/z 100 000 by laser ionization time-of flight mass spectrometry.Crossref | GoogleScholarGoogle Scholar |

[9]  M Dole, LL Mack, RL Hines, RC Mobley, LD Ferguson, MB Alice, Molecular beams of macroions. J Chem Phys 1968, 49, 2240.
         | Molecular beams of macroions.Crossref | GoogleScholarGoogle Scholar |

[10]  JB Fenn, M Mann, CK Meng, SF Wong, CM Whitehouse, Electrospray ionization for mass spectrometry of large biomolecules. Science 1989, 246, 64.
         | Electrospray ionization for mass spectrometry of large biomolecules.Crossref | GoogleScholarGoogle Scholar |

[11]  Initial sequencing and analysis of the human genome. Nature 2001, 409, 860.
         | Initial sequencing and analysis of the human genome.Crossref | GoogleScholarGoogle Scholar |

[12]  JC Venter, MD Adams, EW Myers, PW Li, RJ Mural, GG Sutton, HO Smith, M Yandell, CA Evans, et al. The sequence of the human genome. Science 2001, 291, 1304.
         | The sequence of the human genome.Crossref | GoogleScholarGoogle Scholar |

[13]  Tanford C, Reynolds JA. Nature’s robots: a history of proteins. New York, NY: Oxford University Press; 2001. pp. 1–304.

[14]  JS Fruton, Early theories of protein structure. Ann N Y Acad Sci 1979, 325, 1.
         | Early theories of protein structure.Crossref | GoogleScholarGoogle Scholar |

[15]  F Sanger, Chemistry of insulin: determination of the structure of insulin opens the way to greater understanding of life processes. Science 1959, 129, 1340.
         | Chemistry of insulin: determination of the structure of insulin opens the way to greater understanding of life processes.Crossref | GoogleScholarGoogle Scholar |

[16]  Taylor JF. The isolation of proteins. In: Neurath H, Bailey K, editors. The Proteins. Vol. 1A . Academic Press; 1953; pp. 1–85.

[17]  Zittle CA. Adsorption studies of enzymes and other proteins. In: Nord FF, editor. Advances in Enzymology and Related Areas of Molecular Biology. Vol. 14. John Wiley & Sons, Ltd; 1953. pp. 319–374.

[18]  LS Ettre, 75 years of chromatography: a glimpse behind the scenes. J High Resol Chromatogr 1979, 2, 500.
         | 75 years of chromatography: a glimpse behind the scenes.Crossref | GoogleScholarGoogle Scholar |

[19]  AJP Martin, RLM Synge, Analytical chemistry of the proteins. Adv Protein Chem 1945, 2, 1.
         | Analytical chemistry of the proteins.Crossref | GoogleScholarGoogle Scholar |

[20]  S Paléus, JB Neilands, Preparation of cytochrome c with the aid of ion exchange resin. Acta Chem Scand 1950, 4, 1024.
         | Preparation of cytochrome c with the aid of ion exchange resin.Crossref | GoogleScholarGoogle Scholar |

[21]  CHW Hirs, WH Stein, S Moore, Chromatography of proteins. Ribonuclease. J Am Chem Soc 1951, 73, 1893.
         | Chromatography of proteins. Ribonuclease.Crossref | GoogleScholarGoogle Scholar |

[22]  S Moore, DH Spackman, WH Stein, Chromatography of amino acids on sulfonated polystyrene resins. An improved system. Anal Chem 1958, 30, 1185.
         | Chromatography of amino acids on sulfonated polystyrene resins. An improved system.Crossref | GoogleScholarGoogle Scholar |

[23]  Bradshaw RA. Protein sequence determination: methodology and evolutionary implications. In: Bradshaw RA, Hart GW, Stahl PD, editors. Encyclopedia of Cell Biology, Oxford, UK: Elsevier Vol. 1, 2nd edn. 2023. pp. 86–95.

[24]  B Lindqvist, T Storgårds, Molecular-sieving properties of starch. Nature 1955, 175, 511.
         | Molecular-sieving properties of starch.Crossref | GoogleScholarGoogle Scholar |

[25]  GH Lathe, CRJ Ruthven, The separation of substances and estimation of their relative molecular sizes by the use of columns of starch in water. Biochem J 1956, 62, 665.
         | The separation of substances and estimation of their relative molecular sizes by the use of columns of starch in water.Crossref | GoogleScholarGoogle Scholar |

[26]  J Porath, P Flodin, Gel filtration: a method for desalting and group separation. Nature 1959, 183, 1657.
         | Gel filtration: a method for desalting and group separation.Crossref | GoogleScholarGoogle Scholar |

[27]  Determann H. Gel chromatography. New York, NY: Springer-Verlag; 1968. pp. 1–195.

[28]  Scopes RK. Protein Purification: Principles and Practice, 2nd edn. New York: Springer-Verlag; 1987; pp. 1–329.

[29]  O Vesterberg, History of electrophoretic methods. J Chromatogr 1989, 480, 3.
         | History of electrophoretic methods.Crossref | GoogleScholarGoogle Scholar |

[30]  A Tiselius, XLV. Electrophoresis of serum globulin. I. Biochem J 1937, 31, 313.
         | XLV. Electrophoresis of serum globulin. I.Crossref | GoogleScholarGoogle Scholar |

[31]  A Tiselius, CLXXXII. Electrophoresis of serum globulin. II. Electrophoretic analysis of normal and immune sera. Biochem J 1937, 31, 1464.
         | CLXXXII. Electrophoresis of serum globulin. II. Electrophoretic analysis of normal and immune sera.Crossref | GoogleScholarGoogle Scholar |

[32]  F Sanger, S Nicklen, AR Coulson, DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977, 74, 5463.
         | DNA sequencing with chain-terminating inhibitors.Crossref | GoogleScholarGoogle Scholar |

[33]  J Margolis, KG Kenrick, Two-dimensional resolution of plasma proteins by combination of polyacrylamide disc and gradient gel electrophoresis. Nature 1969, 221, 1056.
         | Two-dimensional resolution of plasma proteins by combination of polyacrylamide disc and gradient gel electrophoresis.Crossref | GoogleScholarGoogle Scholar |

[34]  G Dale, AL Latner, Isoelectric focusing of serum proteins in acrylamide gels followed by electrophoresis. Clin Chim Acta 1969, 24, 61.
         | Isoelectric focusing of serum proteins in acrylamide gels followed by electrophoresis.Crossref | GoogleScholarGoogle Scholar |

[35]  V Macko, H Stegemann, Mapping of potato proteins by combined electrofocusing and electrophoresis identification of varieties. Hoppe Seylers Z Physiol Chem 1969, 350, 917.

[36]  H Stegemann, Protein mapping in polyacrylamide and its application to genetic analysis in plants. Angew Chem Int Ed Engl 1970, 9, 643.
         | Protein mapping in polyacrylamide and its application to genetic analysis in plants.Crossref | GoogleScholarGoogle Scholar |

[37]  GA Scheele, Two-dimensional gel analysis of soluble proteins. Characterization of guinea pig exocrine pancreatic proteins. J Biol Chem 1975, 250, 5375.
         | Two-dimensional gel analysis of soluble proteins. Characterization of guinea pig exocrine pancreatic proteins.Crossref | GoogleScholarGoogle Scholar |

[38]  P Edman, Method for determination of the amino acid sequence in peptides. Acta Chem Scand 1950, 4, 283.
         | Method for determination of the amino acid sequence in peptides.Crossref | GoogleScholarGoogle Scholar |

[39]  W Konigsberg, RJ Hill, The structure of human hemoglobin. III. The sequence of amino acids in the tryptic peptides of the α chain. J Biol Chem 1962, 237, 2547.
         | The structure of human hemoglobin. III. The sequence of amino acids in the tryptic peptides of the α chain.Crossref | GoogleScholarGoogle Scholar |

[40]  Blackburn S. Protein sequence determination: methods and techniques. New York: Marcel Dekker; 1970. pp. 1–292.

[41]  P Edman, G Begg, A protein sequenator. Eur J Biochem 1967, 1, 80.
         | A protein sequenator.Crossref | GoogleScholarGoogle Scholar |

[42]  RM Hewick, MW Hunkapiller, LE Hood, WJ Dreyer, A gas-liquid solid phase peptide and protein sequenator. J Biol Chem 1981, 256, 7990.
         | A gas-liquid solid phase peptide and protein sequenator.Crossref | GoogleScholarGoogle Scholar |

[43]  CHW Hirs, S Moore, WH Stein, The sequence of the amino acid residues in performic acid-oxidized ribonuclease. J Biol Chem 1960, 235, 633.
         | The sequence of the amino acid residues in performic acid-oxidized ribonuclease.Crossref | GoogleScholarGoogle Scholar |

[44]  S Akabori, K Ohno, K Narita, On the hydrazinolysis of proteins and peptides: a method for the characterization of carboxyl-terminal amino acid. Bull Chem Soc Jpn 1952, 25, 214.
         | On the hydrazinolysis of proteins and peptides: a method for the characterization of carboxyl-terminal amino acid.Crossref | GoogleScholarGoogle Scholar |

[45]  E Gross, B Witkop, Selective cleavage of the methionyl peptide bonds in ribonuclease with cyanogen bromide. J Am Chem Soc 1961, 83, 1510.
         | Selective cleavage of the methionyl peptide bonds in ribonuclease with cyanogen bromide.Crossref | GoogleScholarGoogle Scholar |

[46]  Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual, 2nd edn. Cold Springs Harbor, NY: Cold Springs Harbor Laboratory Press; 1989. pp. 1–1546.

[47]  AM Maxam, W Gilbert, A new method for sequencing DNA. Proc Natl Acad Sci 1977, 74, 560.
         | A new method for sequencing DNA.Crossref | GoogleScholarGoogle Scholar |

[48]  Shen C-H, editor. Techniques in Sequencing in Diagnostic Molecular Biology. NY: Academic Press; 2019. pp. 277–301.

[49]  Y Cheng, N Grigorieff, PA Penczek, T Walz, A primer to single-particle cryo-electron microscopy. Cell 2015, 161, 438.
         | A primer to single-particle cryo-electron microscopy.Crossref | GoogleScholarGoogle Scholar |

[50]  JD Bernal, D Crowfoot, X-ray photographs of crystalline pepsin. Nature 1934, 133, 794.
         | X-ray photographs of crystalline pepsin.Crossref | GoogleScholarGoogle Scholar |

[51]  Blundell TL, Johnson LN. Protein Crystallography. New York: Academic Press; 1976. pp. 1–565.

[52]  JC Kendrew, G Bodo, HM Dintzis, RG Parrish, H Wyckoff, DC Phillips, A three-dimensional model of the myoglobin molecule obtained by X-ray analysis. Nature 1958, 181, 662.
         | A three-dimensional model of the myoglobin molecule obtained by X-ray analysis.Crossref | GoogleScholarGoogle Scholar |

[53]  JC Kendrew, RE Dickerson, BE Strandberg, RG Hart, DR Davies, DC Phillips, VC Shore, Structure of myoglobin: a three-dimensional Fourier synthesis at 2 Å resolution. Nature 1960, 185, 422.
         | Structure of myoglobin: a three-dimensional Fourier synthesis at 2 Å resolution.Crossref | GoogleScholarGoogle Scholar |

[54]  MF Perutz, MG Rossmann, AF Cullis, H Muirhead, G Will, ACT North, Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-Å. Resolution, obtained by X-ray analysis. Nature 1960, 185, 416.
         | Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-Å. Resolution, obtained by X-ray analysis.Crossref | GoogleScholarGoogle Scholar |

[55]  MF Perutz, H Muirhead, JM Cox, LCG Goaman, Three-dimensional Fourier synthesis of horse oxyhaemoglobin at 2.8 Å resolution: the atomic model. Nature 1968, 219, 131.
         | Three-dimensional Fourier synthesis of horse oxyhaemoglobin at 2.8 Å resolution: the atomic model.Crossref | GoogleScholarGoogle Scholar |

[56]  CCF Blake, DF Koenig, GA Mair, ACT North, DC Phillips, VR Sarma, Structure of hen egg-white lysozyme: a three-dimensional Fourier synthesis at 2 Å resolution. Nature 1965, 206, 757.
         | Structure of hen egg-white lysozyme: a three-dimensional Fourier synthesis at 2 Å resolution.Crossref | GoogleScholarGoogle Scholar |

[57]  Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB); https://www.rcsb.org/stats

[58]  TL Blundell, JF Cutfield, SM Cutfield, EJ Dodson, GG Dodson, DC Hodgkin, DA Mercola, M Vijayan, Atomic positions in rhombohedral 2-zinc insulin crystals. Nature 1971, 231, 506.
         | Atomic positions in rhombohedral 2-zinc insulin crystals.Crossref | GoogleScholarGoogle Scholar |

[59]  K Wüthrich, NMR studies of structure and function of biological macromolecules (Nobel Lecture). J Biomol NMR 2003, 27, 13.
         | NMR studies of structure and function of biological macromolecules (Nobel Lecture).Crossref | GoogleScholarGoogle Scholar |

[60]  G Münzenberg, Development of mass spectrometers from Thomson and Aston to present. Int J Mass Spectrom 2013, 349–350, 9.
         | Development of mass spectrometers from Thomson and Aston to present.Crossref | GoogleScholarGoogle Scholar |

[61]  A Chodas, April 1946: first concept of time-of-flight mass spectrometer. Amer Phys Soc News 2001, 10,

[62]  K Biemann, Structure determination of natural products by mass spectrometry. Annu Rev Anal Chem 2015, 8, 1.
         | Structure determination of natural products by mass spectrometry.Crossref | GoogleScholarGoogle Scholar |

[63]  C-O Andersson, Mass spectrometric studies on amino acid and peptide derivatives. Acta Chem Scand 1958, 12, 1353.
         | Mass spectrometric studies on amino acid and peptide derivatives.Crossref | GoogleScholarGoogle Scholar |

[64]  K Biemann, Laying the groundwork for proteomics: mass spectrometry from 1958 to 1988. Int J Mass Spectrom 2007, 259, 1.
         | Laying the groundwork for proteomics: mass spectrometry from 1958 to 1988.Crossref | GoogleScholarGoogle Scholar |

[65]  G Hudson, K Biemann, Mass spectrometric sequencing of proteins. The structure of subunit I of monellin. Biochem Biophys Res Commun 1976, 71, 212.
         | Mass spectrometric sequencing of proteins. The structure of subunit I of monellin.Crossref | GoogleScholarGoogle Scholar |

[66]  HG Khorana, GE Gerber, WC Herlihy, CP Gray, RJ Anderegg, K Nihei, K Biemann, Amino acid sequence of bacteriorhodopsin. Proc Natl Acad Sci U S A 1979, 76, 5046.
         | Amino acid sequence of bacteriorhodopsin.Crossref | GoogleScholarGoogle Scholar |

[67]  M Barber, RS Bordoli, RD Sedgwick, AN Tyler, Fast atom bombardment of solids (F.A.B.): a new ion source for mass spectrometry. J Chem Soc Chem Commun 1981, 325.
         | Fast atom bombardment of solids (F.A.B.): a new ion source for mass spectrometry.Crossref | GoogleScholarGoogle Scholar |

[68]  TW Shannon, FW McLafferty, Identification of gaseous organic ions by the use of “metastable peaks”. J Am Chem Soc 1966, 88, 5021.
         | Identification of gaseous organic ions by the use of “metastable peaks”.Crossref | GoogleScholarGoogle Scholar |

[69]  DF Hunt, JR Yates III, J Shabanowitz, S Winston, CR Hauer, Protein sequencing by tandem mass spectrometry. Proc Natl Acad Sci U S A 1986, 83, 6233.
         | Protein sequencing by tandem mass spectrometry.Crossref | GoogleScholarGoogle Scholar |

[70]  P Roepstorff, J Fohlman, Proposal for a common nomenclature for sequence ions in mass spectra of peptides. Biomed Mass Spectrom 1984, 11, 601.
         | Proposal for a common nomenclature for sequence ions in mass spectra of peptides.Crossref | GoogleScholarGoogle Scholar |

[71]  R Aebersold, DR Goodlett, Mass spectrometry in proteomics. Chem Rev 2001, 101, 269.
         | Mass spectrometry in proteomics.Crossref | GoogleScholarGoogle Scholar |

[72]  WJ Henzel, TM Billeci, JT Stults, SC Wong, C Grimley, C Watanabe, Identifying proteins from two-dimensional gels by molecular mass searching of peptide fragments in protein sequence databases. Proc Natl Acad Sci U S A 1993, 90, 5011.
         | Identifying proteins from two-dimensional gels by molecular mass searching of peptide fragments in protein sequence databases.Crossref | GoogleScholarGoogle Scholar |

[73]  P James, M Quadroni, E Carafoli, G Gonnet, Protein identification by mass profile fingerprinting. Biochem Biophys Res Commun 1993, 195, 58.
         | Protein identification by mass profile fingerprinting.Crossref | GoogleScholarGoogle Scholar |

[74]  M Mann, P Højrup, P Roepstorff, Use of mass spectrometric molecular weight information to identify proteins in sequence databases. Biol Mass Spectrom 1993, 22, 338.
         | Use of mass spectrometric molecular weight information to identify proteins in sequence databases.Crossref | GoogleScholarGoogle Scholar |

[75]  DJC Pappin, P Hojrup, AJ Bleasby, Rapid identification of proteins by peptide-mass fingerprinting. Current Biol 1993, 3, 327.
         | Rapid identification of proteins by peptide-mass fingerprinting.Crossref | GoogleScholarGoogle Scholar |

[76]  JR Yates, S Speicher, PR Griffin, T Hunkapiller, Peptide mass maps: a highly informative approach to protein identification. Anal Biochem 1993, 214, 397.
         | Peptide mass maps: a highly informative approach to protein identification.Crossref | GoogleScholarGoogle Scholar |

[77]  A Shevchenko, ON Jensen, AV Podtelejnikov, F Sagliocco, M Wilm, O Vorm, P Mortensen, A Shevchenko, H Boucherie, M Mann, Linking genome and proteome by mass spectrometry: large-scale identification of yeast proteins from two dimensional gels. Proc Natl Acad Sci U S A 1996, 93, 14440.
         | Linking genome and proteome by mass spectrometry: large-scale identification of yeast proteins from two dimensional gels.Crossref | GoogleScholarGoogle Scholar |

[78]  JK Eng, AL McCormack, JR Yates, An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database. J Am Soc Mass Spectrom 1994, 5, 976.
         | An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database.Crossref | GoogleScholarGoogle Scholar |

[79]  H Steen, M Mann, The abc’S (and xyz’S) of peptide sequencing. Nat Rev Mol Cell Biol 2004, 5, 699.
         | The abc’S (and xyz’S) of peptide sequencing.Crossref | GoogleScholarGoogle Scholar |

[80]  AD Catherman, OS Skinner, NL Kelleher, Top down proteomics: facts and perspectives. Biochem Biophys Res Commun 2014, 445, 683.
         | Top down proteomics: facts and perspectives.Crossref | GoogleScholarGoogle Scholar |

[81]  PB Pandeswari, V Sabareesh, Middle-down approach: a choice to sequence and characterize proteins/proteomes by mass spectrometry. RSC Adv 2019, 9, 313.
         | Middle-down approach: a choice to sequence and characterize proteins/proteomes by mass spectrometry.Crossref | GoogleScholarGoogle Scholar |

[82]  EG Krebs, EH Fischer, The phosphorylase b to a converting enzyme of rabbit skeletal muscle. Biochim Biophys Acta 1956, 20, 150.
         | The phosphorylase b to a converting enzyme of rabbit skeletal muscle.Crossref | GoogleScholarGoogle Scholar |

[83]  T Hunter, Signaling 2000 and beyond. Cell 2000, 100, 113.
         | Signaling 2000 and beyond.Crossref | GoogleScholarGoogle Scholar |

[84]  P Vlastaridis, P Kyriakidou, A Chaliotis, Y Van de Peer, SG Oliver, GD Amoutzias, Estimating the total number of phosphoproteins and phosphorylation sites in eukaryotic proteomes. GigaScience 2017, 6, giw015.
         | Estimating the total number of phosphoproteins and phosphorylation sites in eukaryotic proteomes.Crossref | GoogleScholarGoogle Scholar |

[85]  H Zhu, M Bilgin, M Snyder, Proteomics. Annu Rev Biochem 2003, 72, 783.
         | Proteomics.Crossref | GoogleScholarGoogle Scholar |

[86]  S Fields, O-k Song, A novel genetic system to detect protein–protein interactions. Nature 1989, 340, 245.
         | A novel genetic system to detect protein–protein interactions.Crossref | GoogleScholarGoogle Scholar |

[87]  P Uetz, L Giot, G Cagney, TA Mansfield, RS Judson, JR Knight, D Lockshon, V Narayan, M Srinivasan, P Pochart, A Qureshi-Emili, Y Li, B Godwin, D Conover, T Kalbfleisch, G Vijayadamodar, M Yang, M Johnston, S Fields, JM Rothberg, A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae. Nature 2000, 403, 623.
         | A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae.Crossref | GoogleScholarGoogle Scholar |

[88]  T Ito, T Chiba, R Ozawa, M Yoshida, M Hattori, Y Sakaki, A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci U S A 2001, 98, 4569.
         | A comprehensive two-hybrid analysis to explore the yeast protein interactome.Crossref | GoogleScholarGoogle Scholar |

[89]  AC Gavin, M Bösche, R Krause, P Grandi, M Marzioch, A Bauer, J Schultz, JM Rick, A-M Michon, C-M Cruciat, M Remor, C Höfert, M Schelder, M Brajenovic, H Ruffner, A Merino, K Klein, M Hudak, D Dickson, T Rudi, V Gnau, A Bauch, S Bastuck, B Huhse, C Leutwein, M-A Heurtier, RR Copley, A Edelmann, E Querfurth, V Rybin, G Drewes, M Raida, T Bouwmeester, P Bork, B Seraphin, B Kuster, G Neubauer, G Superti-Furga, Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 2002, 415, 141.
         | Functional organization of the yeast proteome by systematic analysis of protein complexes.Crossref | GoogleScholarGoogle Scholar |

[90]  Y Ho, A Gruhler, A Heilbut, GD Bader, L Moore, S-L Adams, A Millar, P Taylor, K Bennett, K Boutilier, L Yang, C Wolting, I Donaldson, S Schandorff, J Shewnarane, M Vo, J Taggart, M Goudreault, B Muskat, C Alfarano, D Dewar, Z Lin, K Michalickova, AR Willems, H Sassi, PA Nielsen, KJ Rasmussen, JR Andersen, LE Johansen, LH Hansen, H Jespersen, A Podtelejnikov, E Nielsen, J Crawford, V Poulsen, BD Sørensen, J Matthiesen, RC Hendrickson, F Gleeson, T Pawson, MF Moran, D Durocher, M Mann, CWV Hogue, D Figeys, M Tyers, Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 2002, 415, 180.
         | Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry.Crossref | GoogleScholarGoogle Scholar |

[91]  R-P Huang, R Huang, Y Fan, Y Lin, Simultaneous detection of multiple cytokines from conditioned media and patient’s sera by an antibody-based protein array system. Anal Biochem 2001, 294, 55.
         | Simultaneous detection of multiple cytokines from conditioned media and patient’s sera by an antibody-based protein array system.Crossref | GoogleScholarGoogle Scholar |

[92]  R Wiese, Y Belosludtsev, T Powdrill, P Thompson, M Hogan, Simultaneous multianalyte ELISA performed on a microarray platform. Clin Chem 2001, 47, 1451.
         | Simultaneous multianalyte ELISA performed on a microarray platform.Crossref | GoogleScholarGoogle Scholar |

[93]  RA Bradshaw, H Hondermarck, H Rodriguez, Cancer proteomics and the elusive diagnostic biomarkers. Proteomics 2019, 19, 1800445.
         | Cancer proteomics and the elusive diagnostic biomarkers.Crossref | GoogleScholarGoogle Scholar |