Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network
Abstract
:1. Introduction
2. Materials and Methods
2.1. Acquisition of Data
2.2. Annotation Enrichment/Over-Representation Analysis
2.3. Construction of Protein–Protein/Gene–Gene Interaction (PPI) Networks
2.4. Characterization of Topological Properties of Networks
2.4.1. Degree Distribution, p(k)
2.4.2. Clustering Coefficient, c(k)
2.4.3. Neighborhood Connectivity Distribution, CN(k)
2.4.4. Closeness Centrality, CC(k)
2.4.5. Eigenvector Centrality, CE(k)
2.4.6. Betweenness Centrality, CB(k)
2.5. MCODE (Molecular Complex Detection)-Derived Protein Complexes to Filter Drug-Actionable Genes in the Network
2.6. Detection of Key Regulators (KRs)
2.7. Knockout Experiment
2.8. Validation of Expression Patterns
3. Results
3.1. Data Acquisition and Principal Dementia Network
3.2. Gene-Ontology-Based Overrepresentation Analysis
3.3. Alzheimer’s Disease and Other Dementias’ PPI Networks Exhibit Hierarchical, Scale-free Topologies
3.4. Filtering Drug-Actionable Genes for Noise through Dense Clusters Obtained from the PDN
3.5. Key Regulators
3.6. Assessment of the Network’s Stability
3.7. Interaction Analysis of Druggable Genome and Network’s Stability
3.8. Validation of Key Regulators’ Expression Patterns
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Name | Gene Ontology Annotation | Degree (k) | c(k) | CN(k) | CB(k) | CC(k) | CE(k) |
---|---|---|---|---|---|---|---|---|
UBC | ubiquitin C | protease binding | 88 | 0.419801 | 45.125 | 0.025 | 0.84375 | 0.171251 |
EGFR | epidermal growth factor receptor | identical protein binding and protein kinase activity | 72 | 0.475352 | 48.08333 | 0.013 | 0.75 | 0.148904 |
APP | amyloid beta precursor protein | identical protein binding and enzyme binding | 66 | 0.454079 | 47.07576 | 0.012 | 0.72 | 0.133501 |
CTNNB1 | catenin beta 1 | DNA-binding transcription factor activity and binding | 68 | 0.473661 | 47.98529 | 0.012 | 0.72973 | 0.140163 |
NTRK1 | neurotrophic receptor tyrosine kinase 1 | protein homodimerization activity and protein kinase activity | 65 | 0.465865 | 47.30769 | 0.012 | 0.715232 | 0.132686 |
FN1 | fibronectin 1 | heparin binding and protease binding | 63 | 0.461342 | 47.28571 | 0.011 | 0.705882 | 0.128571 |
HSP90AA1 | heat shock protein 90kDa alpha family class A member 1 | identical protein binding | 67 | 0.483492 | 48.20896 | 0.010 | 0.724832 | 0.139365 |
MDM2 | MDM2 proto-oncogene | identical protein binding and ligase activity | 59 | 0.456458 | 46.86441 | 0.010 | 0.687898 | 0.119216 |
VCP | valosin-containing protein | signaling receptor binding | 61 | 0.477049 | 47.95082 | 0.010 | 0.696774 | 0.125994 |
CTNNA1 | catenin alpha 1 | actin filament binding | 58 | 0.455535 | 47.2069 | 0.010 | 0.683544 | 0.117217 |
GRB2 | growth factor receptor-bound protein 2 | protein kinase binding | 61 | 0.472678 | 47.77049 | 0.010 | 0.696774 | 0.125459 |
Gene | Name | Gene Ontology Annotation | Degree (k) | c(k) | CN(k) | CB(k) | CC(k) | CE(k) |
---|---|---|---|---|---|---|---|---|
ANK2 | ankyrin 2, neuronal | protein kinase binding and structural constituent of cytoskeleton | 153 | 0.23787 | 164.797 | 9.84 × 10−4 | 0.54624 | 0.03467 |
APAF1 | apoptotic peptidase activating factor 1 | identical protein binding and ADP binding | 131 | 0.23864 | 163.863 | 7.37 × 10−4 | 0.53922 | 0.02975 |
BAG2 | BCL2 associated athanogene 2 | identical protein binding and chaperone binding | 137 | 0.25537 | 165.263 | 8.11 × 10−4 | 0.54121 | 0.03184 |
CCL5 | C-C motif chemokine ligand 5 | protein homodimerization activity and chemokine activity | 126 | 0.36648 | 158.738 | 4.94 × 10−4 | 0.53528 | 0.0271 |
CD4 | CD4 molecule | protein homodimerization activity and enzyme binding | 148 | 0.25896 | 162.304 | 0.00104 | 0.54321 | 0.03311 |
CELF2 | CUGBP, Elav-like family member 2 | nucleic acid binding and RNA binding | 278 | 0.23663 | 163.838 | 0.00327 | 0.59259 | 0.06322 |
CTNNA3 | catenin alpha 3 | structural molecule activity and beta–catenin binding | 205 | 0.24017 | 161.654 | 0.0022 | 0.56374 | 0.04577 |
DNAJB1 | DnaJ heat shock protein family (Hsp40) member B1 | unfolded protein binding and ATPase binding | 125 | 0.25639 | 163.832 | 6.87 × 10−4 | 0.5379 | 0.02853 |
EGFR | epidermal growth factor receptor | identical protein binding and protein kinase activity | 316 | 0.23984 | 165.997 | 0.004 | 0.609 | 0.07338 |
FGF1 | fibroblast growth factor 1 | growth factor activity and Hsp70 protein binding | 153 | 0.2254 | 158.529 | 0.00113 | 0.54591 | 0.03315 |
FYN | FYN proto-oncogene, Src family tyrosine kinase | transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity | 231 | 0.26934 | 172.139 | 0.00204 | 0.57516 | 0.05493 |
HDAC9 | histone deacetylase 9 | transcription factor binding and histone deacetylase binding | 122 | 0.27476 | 176.23 | 5.79 × 10−4 | 0.53528 | 0.02986 |
HSF1 | heat shock transcription factor 1 | DNA-binding transcription factor activity and chromatin binding | 92 | 0.3022 | 166.761 | 2.95 × 10−4 | 0.52569 | 0.02156 |
HSP90AA1 | heat shock protein 90kDa alpha family class A member 1 | identical protein binding | 293 | 0.27411 | 172.635 | 0.00305 | 0.59823 | 0.07174 |
HSP90AB1 | heat shock protein 90kDa alpha family class B member 1 | protein kinase binding | 207 | 0.30772 | 176.865 | 0.0015 | 0.56519 | 0.05223 |
HSPA1A | heat shock protein family A (Hsp70) member 1A | ubiquitin protein ligase binding | 108 | 0.35722 | 193.324 | 3.41 × 10−4 | 0.53108 | 0.02952 |
IL34 | interleukin 34 | cytokine activity and macrophage colony-stimulating factor receptor binding | 32 | 0.22379 | 160.719 | 4.95 × 10−5 | 0.50372 | 0.00696 |
JUN | Jun proto-oncogene, AP-1 transcription factor subunit | sequence-specific DNA binding | 298 | 0.23117 | 161.597 | 0.00383 | 0.59986 | 0.06713 |
LCK | LCK proto-oncogene, Src family tyrosine kinase | identical protein binding and protein kinase activity | 150 | 0.30318 | 174.307 | 7.34 × 10−4 | 0.54422 | 0.03627 |
LRP6 | LDL receptor related protein 6 | protein homodimerization activity and signaling receptor binding | 98 | 0.23312 | 159.214 | 7.21 × 10−4 | 0.52695 | 0.02125 |
NF1 | neurofibromin 1 | binding and phosphatidylcholine binding | 119 | 0.2286 | 162.832 | 6.87 × 10−4 | 0.53495 | 0.02656 |
NOS2 | nitric oxide synthase 2 | protein homodimerization activity and oxidoreductase activity | 107 | 0.23911 | 165.486 | 6.23 × 10−4 | 0.53012 | 0.02444 |
RIN3 | Ras and Rab interactor 3 | GTPase activator activity and Rab guanyl–nucleotide exchange factor activity | 43 | 0.29236 | 158.86 | 7.03 × 10−5 | 0.50286 | 0.00939 |
RPS6KB2 | ribosomal protein S6 kinase B2 | transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity | 112 | 0.27622 | 163.482 | 4.95 × 10−4 | 0.52916 | 0.02593 |
TXNIP | thioredoxin interacting protein | ubiquitin protein ligase binding and enzyme inhibitor activity | 166 | 0.25936 | 171.554 | 9.43 × 10−4 | 0.55103 | 0.03948 |
UBE4A | ubiquitination factor E4A | ligase activity and ubiquitin–ubiquitin ligase activity | 188 | 0.23603 | 158.957 | 0.00151 | 0.55802 | 0.04172 |
VLDLR | very low-density lipoprotein receptor | calcium ion binding | 139 | 0.23762 | 162.698 | 8.79 × 10−4 | 0.54087 | 0.03118 |
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Lalwani, A.K.; Krishnan, K.; Bagabir, S.A.; Alkhanani, M.F.; Almalki, A.H.; Haque, S.; Sharma, S.K.; Singh, R.K.B.; Malik, M.Z. Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network. Biomolecules 2022, 12, 451. https://doi.org/10.3390/biom12030451
Lalwani AK, Krishnan K, Bagabir SA, Alkhanani MF, Almalki AH, Haque S, Sharma SK, Singh RKB, Malik MZ. Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network. Biomolecules. 2022; 12(3):451. https://doi.org/10.3390/biom12030451
Chicago/Turabian StyleLalwani, Amit Kumar, Kushagra Krishnan, Sali Abubaker Bagabir, Mustfa F. Alkhanani, Atiah H. Almalki, Shafiul Haque, Saurabh Kumar Sharma, R. K. Brojen Singh, and Md. Zubbair Malik. 2022. "Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network" Biomolecules 12, no. 3: 451. https://doi.org/10.3390/biom12030451