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Protein-protein interaction networks and biology—what's the connection?

Hakes, Luke, Pinney, John W, Robertson, David L, Lovell, Simon C·2008·Nature Biotechnology

DOI 10.1038/nbt0108-69

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“In the living system, protein–protein interactions lead to pharmacological damage due to the synergistic effect [85].”
Background
Cliques in mitotic spindle network bring kinetochore‐associated complexes to form dependence pathway
Chen, T.-C., Lee, S., Chan, C., Juang, Y., Hong, Y., Huang, Y.-H., Lai, J., Kao, C., & Huang, C. F. (2009) · PROTEOMICS · doi:10.1002/pmic.200900231 · Cited by 12
“However, large-scale PPI studies are the major source to provide the potential targets among the enormous number of unknown proteins and missing links in the network [13].”
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Molecular property diagnostic suite (MPDS): Development of disease-specific open source web portals for drug discovery
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“A completely constructed interactome with all possible molecular interactions could form a base to understand human disease networks [26].”
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Difference in gene duplicability may explain the difference in overall structure of protein-protein interaction networks among eukaryotes
Hase, T., Niimura, Y., & Tanaka, H. (2010) · BMC Evolutionary Biology · doi:10.1186/1471-2148-10-358 · Cited by 12
“[28] pointed out that multiple validation introduces another problem: interactions observed at least twice will be biased towards well-studied proteins, such as those from particular cellular environments or highly expressed ones.”
Background
The properties of hub proteins in a yeast‐aggregated cell cycle network and its phase sub‐networks
Wu, X., Guo, J., Zhang, D., & Lin, K. (2009) · PROTEOMICS · doi:10.1002/pmic.200900053 · Cited by 12
“In conclusion, the analysis of dynamic architecture of the cell cycle subsystem can serve as a supplement for the current studies of the yeast cell cycle and will be helpful for understanding the complete network topology underlying the molecular machinery of complex phenotypes [38].”
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Evolutionary Characteristics of Bacterial Two-Component Systems
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“More generally, defining what is meant by a system is always going to be based on ad-hoc and potentially subjective criteria [9–13].”
BackgroundSelf-citation
Identification of Protein–Protein Interaction Associated Functions Based on Gene Ontology
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“Protein–protein interactions (PPIs) encompass any direct or indirect biochemical events associated with two or more proteins, featuring functional relevance [1–3].”
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Fang, H., & Gough, J. (2013) · Molecular BioSystems · doi:10.1039/c3mb25495j · Cited by 10
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Maximum Likelihood Inference of the Evolutionary History of a PPI Network from the Duplication History of Its Proteins
Li, S., Choi, K. P., Wu, T., & Zhang, L. (2013) · IEEE Transactions on Computational Biology and Bioinformatics · doi:10.1109/tcbb.2013.14 · Cited by 10
“We show that for a plausible evolutionary history of a PPI network, its relative quality, measured by the so-called loss number, is independent of the growth parameters of the network and can be computed efficiently.”
Background
NCAE: data-driven representations using a deep network-coherent DNA methylation autoencoder identify robust disease and risk factor signatures
Martínez-Enguita, D., Dwivedi, S. K., Jörnsten, R. J., & Gustafsson, M. (2023) · Briefings in Bioinformatics · doi:10.1093/bib/bbad293 · Cited by 10
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Zhang, Q. E., Li, J., Xie, H., Xue, H., & Wang, Y. (2016) · BMC Bioinformatics · doi:10.1186/s12859-016-1333-x · Cited by 9
“However, existing PPI networks cannot accurately describe the interactions between proteins in specific conditions and have different degrees of false positive and false negative results because most large-scale PPI networks are obtained in different experimental conditions, predicted/extracted using different algorit…”
Background
Promiscuous domains: facilitating stability of the yeast protein–protein interaction network
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“Likewise the set of all known physical interactions may contain both false negatives and false positives [52].”
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“Both links and nodes will be under-sampled, and the sampling is likely to be biased (Hakes et al. 2008).”
Background
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“Since current PPI networks are incomplete and noisy – with many false positive interactions as well as false negative interactions [21, 22] – adding pseudo-edges to the reduced target network can lead to more reliable querying results, as will be demonstrated in our simulation results.”
Result
High-Throughput Analyses and Curation of Protein Interactions in Yeast
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“Table 1 gives an overview on several popular properties described in the literature and online graph collections, e.g., (Batagelj 2009; Doncheva et al. 2012; Hakes et al. 2008; Xu et al. 2011) (The Graph Archive: http://www.graph-archive.org; House of Graphs: http://hog.grinvin.org/).”
Background
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Alvarez‐Ponce, D. (2016) · Briefings in Bioinformatics · doi:10.1093/bib/bbw075 · Cited by 6
NABEECO
Ibragimov, R., Martens, J., Guo, J., & Baumbach, J. (2013) · Genetic and Evolutionary Computation Conference Companion (GECCO Companion) · doi:10.1145/2464576.2464600 · Cited by 6
“Here, we concentrate on protein-protein interaction (PPI) networks, where evolutionary preserved topology infers preservation of biological function [5].”
Background
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Agarwal, S. (2012) · Oxford University Research Archive (ORA) (University of Oxford) · doi:10.5287/ora-xr1x2v5o5 · Cited by 6
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“, the absence of biologically valid interactions from the currently available data sets [8,9,11].”
Background
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“Rob Cross tool is advanced in terms of functionality but membership to Network Roundtable is required.”
BackgroundInfluential
Reconstruction of Network Evolutionary History from Extant Network Topology and Duplication History
Li, S., Choi, K. P., Wu, T., & Zhang, L. (2012) · Lecture notes in computer science · doi:10.1007/978-3-642-30191-9_16 · Cited by 4
“Recent progress in experimental systems biology provides us with an unprecedented amount of genome-wide protein-protein interaction (PPI) data [7].”
Background
Protein-Protein Interaction Networks: Structures, Evolution, and Application to Drug Design
Hase, T., & Niimura, Y. (2012) · IntechOpen eBooks · doi:10.5772/36665 · Cited by 4
“It has been pointed out that genome-wide PIN data identified by high-throughput experiments contains a large number of false positive interactions (Hakes et al. 2008).”
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Krishnan, A., Khan, F. I., Sukumar, S., & Khan, M. K. A. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2279699 · Cited by 4
“The knowledge of the topological and statistical characteristics of interaction networks and their connections to the key proteins helps to better comprehend the interactions between protein targets for drugs and other proteins (Hakes et al., 2008).”
Affinity and Chemical Enrichment for Mass Spectrometry-Based Proteomics Analyses
Adelmant, G., Cardoza, J. D., Ficarro, S. B., Sikorski, T. W., Zhang, Y., & Marto, J. A. (2011) · Springer eBooks · doi:10.1007/978-94-007-0828-0_22 · Cited by 4
Tying new knots in synthetic biology
Karig, D., & Simpson, M. L. (2008) · HFSP journal · doi:10.2976/1.2907240 · Cited by 4
“Thus, the underlying set of reactions which can impact the synthetic circuit, either directly or via competition for cell resources, is large, complex, and difficult to discern (Hakes et al., 2008).”
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“Similar biases have been widely recognized in other biological datasets, including drug–target interactions [45] and protein–protein interactions [46], where they are known to impact the validity and accuracy of computational analyses, machine learning predictions, and downstream interpretations…”
A survey of human histone H1 subtypes interaction networks: Implications for histones H1 functioning
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Structural Determinants of Yeast Protein-Protein Interaction Interface Evolution at the Residue Level
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Transcriptional regulation of the genes involved in protein metabolism and processing inSaccharomyces cerevisiae
Dikicioǧlu, D., Nightingale, D. J. H., Wood, V., Lilley, K. S., & Oliver, S. G. (2019) · FEMS Yeast Research · doi:10.1093/femsyr/foz014 · Cited by 3
Interactions of HIV-1 Proteins as Targets for Developing Anti-HIV-1 Peptides
Chandra, K., Maes, M., & Friedler, A. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.46 · Cited by 3
Module Finding Approaches for Protein Interaction Networks
Aittokallio, T. A. (2009) · IGI Global eBooks · doi:10.4018/978-1-60566-398-2.ch018 · Cited by 3
Random Graph Models and Their Application to Protein–Protein Interaction Networks
Higham, D. J., & Pržulj, N. (2011) · Wiley eBooks · doi:10.1002/9781119970606.ch14 · Cited by 3
“However, this data is known to admit very high levels of uncertainty [5, 8, 17, 18, 45].”
Background
Decoding protein binding plasticity via integrated deep ribosome display and deep learning
Tang, M., Li, J., Li, Z., Cui, J., & Qi, H. (2025) · Communications Biology · doi:10.1038/s42003-025-09160-y · Cited by 2
“Protein interactions commonly exhibit promiscuity, a notable trait that empowers proteins to engage with a wide-ranging array of partners 1 .”
Global Protein Interaction Network for Trypanosoma cruzi.
Azimi, A., Gaudreault, F., Sulea, T., & Salavati, R. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00649 · Cited by 2
From Topology to Phenotype in Protein–Protein Interaction Networks
Pržulj, N. (2010) · Springer eBooks · doi:10.1007/978-1-84996-396-1_3 · Cited by 2
Transcriptome-Wide Gene Expression in a Murine Model of Ventilator-Induced Lung Injury
Zhao, L., Zhu, G., Zhou, C., Wang, H., Yu, L., Xu, Y., Li, X., & Wang, Q. (2021) · Disease Markers · doi:10.1155/2021/5535890 · Cited by 2
“PPI represents the process of forming a protein complex by noncovalent bonding between proteins [14].”
Background
Genome-wide identification, characterization, and expression analysis of the MADS-box gene family in grass pea (Lathyrus sativus) under salt stress conditions
Abdelsattar, M., Nassar, A. E., Mousa, K. H., Hussein, A., El-Baghdady, M. M. S., Radwan, K. H., Ibrahim, M. S., Allali, A. E., Hamwieh, A., Alsamman, A. M., et al. (2025) · BMC Genomics · doi:10.1186/s12864-025-11661-3 · Cited by 2
“The Study of protein interaction networks can provide insights into functional relationships and cellular pathways [53].”
Building a Pluripotency Protein Interaction Network for Embryonic Stem Cells
Ng, P. M. L., & Lufki, T. (2011) · InTech eBooks · doi:10.5772/23634 · Cited by 2
Chromatin Regulation and Gene Centrality Are Essential for Controlling Fitness Pleiotropy in Yeast
Zhou, L., Ma, X., Arbeitman, M. N., & Sun, F. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008086 · Cited by 2
Network Cleansing
Marcatili, P., & Tramontano, A. L. (2009) · IGI Global eBooks · doi:10.4018/978-1-60566-398-2.ch006 · Cited by 2
Random Walk Based Global Feature for Disease Gene Identification
Wei, L., Wu, S., Zhang, J., & Xu, Y. D. (2016) · Communications in computer and information science · doi:10.1007/978-981-10-3005-5_38 · Cited by 2
Structure and resilience of bald eagle roost networks
Watts, B. D., & Dyer, R. J. (2018) · Wildlife Society Bulletin · doi:10.1002/wsb.865 · Cited by 2
“Network analysis has been applied to a variety of biological systems ranging from proteins (Gardner et al. 2003, Hakes et al. 2008), metabolism (Jeong et al. 2000), and food webs (Montoya et al. 2009) to ecosystems (Patten et al. 1990, Manfred 2006), among others.”
Method
Analyses of Complex Genome-Scale Biological Networks
Muley, V. Y., & Acharya, V. (2012) · SpringerBriefs in systems biology · doi:10.1007/978-1-4614-4705-4_5 · Cited by 2
Detection of construction biases in biological databases: the case of miRBasePreprint
Saturnino, G. B., Godinho, C. P. D. S., Fagundes-Lima, D., Silva, A. C. E., & Weber, G. (2014) · arXiv (Cornell University) · doi:10.48550/arxiv.1407.6570 · Cited by 2
“We believe that this substantiates some of the criticism that indis-criminate interpretation of network topology has received recently [38, 39].”
Result
Discovering Distinct Functional Modules of Specific Cancer Types Using Protein-Protein Interaction Networks
Shen, R., Wang, X., & Guda, C. (2015) · BioMed Research International · doi:10.1155/2015/146365 · Cited by 1
“PPI networks represent the cross talk among groups of proteins, which have a wide range of biological implications [1, 2].”
Background
Identification of protein interaction methods from biomedical literature
Jhamb, D., Krishnan, A., Palakal, M., Pandit, Y., Palakal, M. J., & Duraiswamy, P. (2014) · IEEE International Conference on Computational Advances in Bio and Medical Sciences · doi:10.1109/iccabs.2014.6863923 · Cited by 1
Quantifying noise in mass spectrometry and yeast two-hybrid protein interaction detection experiments
Annibale, A., Coolen, A. C. C., & Planell-Morell, N. (2015) · Journal of The Royal Society Interface · doi:10.1098/rsif.2015.0573 · Cited by 2
“Moreover, different experiments measure protein interactions in different ways, which causes further biases [1–3].”
Background
The Graph Landscape
Kennedy, A. D. M., Klein, K., & Nguyen, A. (2015) · International Symposium on Visual Information Communication and Interaction (VINCI) · doi:10.1145/2801040.2801059 · Cited by 1
“There is a wide variety of graph properties that might be relevant for analysis, which are described and used in literature and online services, e.g. [15, 36, 11, 18, 5, 6].”
Background
Gene Networks in Neuropsychiatric Disease
Parikshak, N., & Geschwind, D. H. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800105-9.00011-1 · Cited by 1
A Network Target-based Approach for Evaluating Multicomponent Synergy
Li, S., Ningbo, Z., & Zhang, B. (2010) · Cited by 1
Disease Diagnosis and Management Using Bioinformatics and Cyber-Physical Systems
Rout, T., Mohapatra, A., Kar, M., & Muduly, D. K. (2025) · Studies in big data · doi:10.1007/978-981-97-5734-3_9 · Cited by 1
Evaluating the protein–protein binding via the fast pulling of ligand scheme
Nguyen, H. A., Vu, V. V., Truong, V. K., Huynh, L. K., Lenon, G. B., & Ngo, S. T. (2025) · Chemical Physics Letters · doi:10.1016/j.cplett.2025.142136 · Cited by 1
Applications of the In Vitro Virus (IVV) Method for Various Protein Functional Analyses
Tabata, N., Horisawa, K., & Yanagaw, H. (2013) · InTech eBooks · doi:10.5772/55483 · Cited by 1
Identifying Hub Proteins and Their Essentiality from Protein-protein Interaction Network
Bakar, S. A., Taheri, J., & Zomaya, A. Y. (2011) · IEEE International Conference on Bioinformatics and Bioengineering (BIBE) · doi:10.1109/bibe.2011.67 · Cited by 1
“as proven in [8], [9], [10], [11], [12], [27].”
Background
The amyloid interactome 2: mapping protein aggregation
Nastou, K. C., Tsiolaki, P. L., & Iconomidou, V. A. (2019) · Amyloid · doi:10.1080/13506129.2019.1582499 · Cited by 1
“Protein–protein interaction (PPI) networks have long been utilized as tools, in order to gain useful insights into disease mechanisms [2].”
Background
Scalable module detection for attributed networks with applications to breast cancer
Yu, H., & Blair, R. H. (2020) · Journal of Applied Statistics · doi:10.1080/02664763.2020.1803811 · Cited by 1
“Importantly, networks of this type have implicit bias that can manifest in unpredictable ways [18].”
Background
Drug contraindications in comorbid diseases: a protein interactome perspective
Karunakaran, K. B., Ganapathiraju, M. K., Jain, S., Brahmachari, S. K., & Balakrishnan, N. (2024) · Network Modeling Analysis in Health Informatics and Bioinformatics · doi:10.1007/s13721-023-00440-3 · Cited by 1
“Hence, network overlaps may have been underestimated due to the inherent incompleteness of these disease networks, the tendency of incomplete networks to exhibit small overlaps and sampling biases introduced as a result of selective PPI discovery (Hakes et al. 2008).”
Colorectal Cancer and Its Molecular Subsystems: Construction, Interpretation, and Validation
Patel, V. N., & Chance, M. R. (2013) · Wiley eBooks · doi:10.1002/9783527665471.ch7 · Cited by 1
Network-Based Analysis for Biological Knowledge Discovery
Tripathi, L. P., Osorio, R. S. A., Murakami, Y., Chen, Y. A., & Mizuguchi, K. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95502-7.00272-4 · Cited by 1
The reliability of the degree distribution of protein-protein interaction network in different species
Guo, L., Pan, H., Nian, X., & Bing, Z. (2015) · Chinese Control and Decision Conference (CCDC) · doi:10.1109/ccdc.2015.7161910
“On the other hand, the accuracy of experimental PPI data was often questionable [8-10].”
Background
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Authors: Hakes, L., Pinney, J. W., Robertson, D. L., & Lovell, S. C.
Affiliations: University of Manchester (GB)
ORCID: Pinney, John W
Robertson, David L
Lovell, Simon C
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2008-01
Volume: 26
Issue: 1
Pages: 69-72
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt0108-69
OpenAlex: W2165160727
Cited by: 200
References: 37
Citations by year: 2026: 2 · 2025: 9 · 2024: 7 · 2023: 12 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 9 · 2017: 15 · 2016: 13 · 2015: 17 · 2014: 10 · 2013: 17 · 2012: 16
FWCI: 7.96
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders: Wellcome Trust
Biotechnology and Biological Sciences Research Council (BB/F007620/1, BB/C515412/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords: protein-protein interaction network, network analysis
MeSH terms: Algorithms, Binding Sites, Biology, Protein Binding, Sensitivity and Specificity, Signal Transduction, Information Storage and Retrieval, Artifacts, Proteome, Protein Interaction Mapping

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