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Identification of Novel Components of Target-of-Rapamycin Signaling Pathway by Network-Based Multi-Omics Integrative Analysis.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Dereli Eke, Elif 
Arga, Kazim Yalcin 
Eraslan, Serpil 
Erkol, Emir 

Abstract

Target of rapamycin (TOR) is a major signaling pathway and regulator of cell growth. TOR serves as a hub of many signaling routes, and is implicated in the pathophysiology of numerous human diseases, including cancer, diabetes, and neurodegeneration. Therefore, elucidation of unknown components of TOR signaling that could serve as potential biomarkers and drug targets has a great clinical importance. In this study, our aim is to integrate transcriptomics, interactomics, and regulomics data in Saccharomyces cerevisiae using a network-based multiomics approach to enlighten previously unidentified, potential components of TOR signaling. We constructed the TOR-signaling protein interaction network, which was used as a template to search for TOR-mediated rapamycin and caffeine signaling paths. We scored the paths passing from at least one component of TOR Complex 1 or 2 (TORC1/TORC2) using the co-expression levels of the genes in the transcriptome data of the cells grown in the presence of rapamycin or caffeine. The resultant network revealed seven hitherto unannotated proteins, namely, Atg14p, Rim20p, Ret2p, Spt21p, Ylr257wp, Ymr295cp, and Ygr017wp, as potential components of TOR-mediated rapamycin and caffeine signaling in yeast. Among these proteins, we suggest further deciphering of the role of Ylr257wp will be particularly informative in the future because it was the only protein whose removal from the constructed network hindered the signal transduction to the TORC1 effector kinase Npr1p. In conclusion, this study underlines the value of network-based multiomics integrative data analysis in discovering previously unidentified components of the signaling networks by revealing potential components of TOR signaling for future experimental validation.

Description

Keywords

biomarkers, caffeine, drug targets, multiomics, network-based analysis, target of rapamycin (TOR) signaling, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Proteomics, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, TOR Serine-Threonine Kinases

Journal Title

OMICS

Conference Name

Journal ISSN

1536-2310
1557-8100

Volume Title

23

Publisher

Mary Ann Liebert Inc

Rights

All rights reserved
Sponsorship
Leverhulme Trust (ECF-2016-681)