Article: Finding the “switch” in platelet activation prediction of key mediators involved in reversal of platelet activation using a novel network biology approach
Journal of proteomics. 2022 Mar. 23,
2022
Abstract: The cAMP-protein kinase A (PKA) pathway in platelets is important for both platelet activation and inactivation. We hypothesize that proteins/processes downstream of the cAMP-PKA pathway that are regulated after platelet activation ánd subsequent ... ...
Abstract | The cAMP-protein kinase A (PKA) pathway in platelets is important for both platelet activation and inactivation. We hypothesize that proteins/processes downstream of the cAMP-PKA pathway that are regulated after platelet activation ánd subsequent inactivation can serve as a “switch” in platelet activation and inhibition. We used a STRING-based protein-protein interaction network from proteins of interest distilled from publicly available quantitative platelet proteome datasets. The protein network was integrated with biological pathway information by functional enrichment analysis, phosphorylation by PKA, and drug-target information. Functional enrichment analysis revealed biological processes related to vesicle secretion and cytoskeletal reorganization to be overrepresented among these 30 proteins coinciding with topological clusters in the network. Our method identified proteins/processes with functions related to vesicle transport, cyclin-dependent protein kinases, tight junctions, and small GTPases as potential switches in platelet activation and inhibition. Next to established enzymes in cAMP-PKA signaling, such as PDE3A, proteins with an unknown/less well-known role in platelet biology, such as Stonin-2 and ABLIM-3, emerged from our analysis as interesting candidates for reversal of platelet activation. Our method can be used to repurpose existing datasets and provide a coherent overview of mechanisms involved to predict novel connections, by visually integrating multiple datasets. We believe this article presents a novel approach of visually incorporating multiple existing tools and proteomics datasets and in doing so provide a more complete picture of complex molecular mechanisms involved. Using our approach, we also highlight several interesting candidates for future research into the numerous pathologies that incorporate platelet hyperreactivity. |
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Keywords | cytoskeleton ; data collection ; guanosinetriphosphatase ; phosphorylation ; physiological transport ; platelet activation ; prediction ; protein-protein interactions ; proteome ; proteomics ; secretion ; topology |
Language | English |
Dates of publication | 2022-0323 |
Publishing place | Elsevier B.V. |
Document type | Article |
Note | Pre-press version |
ZDB-ID | 2400835-7 |
ISSN | 1876-7737 ; 1874-3919 |
ISSN (online) | 1876-7737 |
ISSN | 1874-3919 |
DOI | 10.1016/j.jprot.2022.104577 |
Database | NAL-Catalogue (AGRICOLA) |
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