Delineation of key regulatory elements identifies points of vulnerability in the mitogen-activated signaling network

Jailkhani, Noor; Ravichandran, Srikanth; Hegde, Shubhada R.; Siddiqui, Zaved; Mande, Shekhar C.; Rao, Kanury V. S.

doi:10.1101/gr.116145.110

Cited by 3 publications

(3 citation statements)

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“…Akt1 is involved in the regulation of cell proliferation and transformation. The wide variety of targets available for Akt1 allows it to stimulate cellular proliferation through myriad downstream substrates with multiple implications on cell-cycle progression and regulation 6 , 11 , 12 . When mitogenic stimulation is provided to mammalian cells in quiescent (G0) stage, a rapid trigger in a number of biochemical signalling cascades is observed.…”

Section: Introductionmentioning

confidence: 99%

Defining the Akt1 interactome and its role in regulating the cell cycle

Duggal

Jailkhani

Midha

et al. 2018

Sci Rep

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Cell growth and proliferation are two diverse processes yet always linked. Akt1, a serine/threonine kinase, is a multi-functional protein implicated in regulation of cell growth, survival and proliferation. Though it has a role in G1/S progression, the manner by which Akt1 controls cell cycle and blends cell growth with proliferation is not well explored. In this study, we characterize the Akt1 interactome as the cell cycle progresses from G0 to G1/S and G2 phase. For this, Akt1-overexpressing HEK293 cells were subjected to AP-MS. To distinguish between individual cell cycle stages, cells were cultured in the light, medium and heavy labelled SILAC media. We obtained 213 interacting partners of Akt1 from these studies. GO classification revealed that a significant number of proteins fall into functional classes related to cell growth or cell cycle processes. Of these, 32 proteins showed varying association with Akt1 in different cell cycle stages. Further analyses uncovered a subset of proteins showing counteracting effects so as to tune stage-specific progression through the cycle. Thus, our study provides some novel perspectives on Akt1-mediated regulation of the cell cycle and offers the framework for a detailed resolution of the downstream cellular mechanisms that are mediated by this kinase.

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Section: Introductionmentioning

confidence: 99%

Defining the Akt1 interactome and its role in regulating the cell cycle

Duggal

Jailkhani

Midha

et al. 2018

Sci Rep

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“…By combining network analysis methods and the RA gene expression profiling data that is present in the GEO database, we can come up with strategies for identifying certain key molecules that are part of the cytokine signaling network. In earlier studies, some efforts have been made to identify key molecules in complex diseases like tuberculosis and cancer using network analysis methods [ 42 – 43 ]. However, such studies are limited in RA.…”

Section: Introductionmentioning

confidence: 99%

A cytokine protein-protein interaction network for identifying key molecules in rheumatoid arthritis

Panga

Raghunathan

2018

PLoS ONE

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Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints. Though the current RA therapeutics such as disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs) and biologics can halt the progression of the disease, none of these would either dramatically reduce or cure RA. So, the identification of potential therapeutic targets and new therapies for RA are active areas of research. Several studies have discovered the involvement of cytokines in the pathogenesis of this disease. These cytokines induce signal transduction pathways in RA synovial fibroblasts (RASF). These pathways share many signal transducers and their interacting proteins, resulting in the formation of a signaling network. In order to understand the involvement of this network in RA pathogenesis, it is essential to identify the key transducers and their interacting proteins that are part of this network. In this study, based on a detailed literature survey, we have identified a list of 12 cytokines that induce signal transduction pathways in RASF. For these cytokines, we have built a signaling network using the protein-protein interaction (PPI) data that was obtained from public repositories such as HPRD, BioGRID, MINT, IntAct and STRING. By combining the network centrality measures with the gene expression data from the RA related microarrays that are available in the open source Gene Expression Omnibus (GEO) database, we have identified 24 key proteins of this signaling network. Two of these 24 are already drug targets for RA, and of the remaining, 12 have direct PPI links to some of the current drug targets of RA. Therefore, these key proteins seem to be crucial in the pathogenesis of RA and hence might be treated as potential drug targets.

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“…So in our quest to understand pleiotropic functions of AKT1 during proliferation, we aim to identify whether it plays any role in CCM. Thus in addition to helping the cells to progress through G1 phase of cell cycle [ 2 ], does it also help the cells to generate mass for division?…”

Section: Introductionmentioning

confidence: 99%

Concurrent interactome and metabolome analysis reveals role of AKT1 in central carbon metabolism

et al. 2018

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ObjectiveSignal transduction not only initiates entry into the cell cycle, but also reprograms the cell’s metabolism. To control abnormalities in cell proliferation, both the aspects should be taken care of, thus pleiotropic signaling molecules are considered as crucial modulators. Considering this, we investigated the role of AKT1 in central carbon metabolism. The role of AKT1 has already been established in the process of cell cycle, but its contribution to the central carbon metabolism is sparsely studied.ResultsTo address this, we combined the metabolomics and proteomics approaches. In accordance to our hypothesis, we found that the AKT1 kinase activity is regulating the levels of acetyl CoA through pyruvate dehydrogenase complex. Further, the decreased levels of acetyl CoA and dependency of acetyl CoA acetyl transferase protein on AKT1 kinase activity was also found to perturb the synthesis rate of palmitic acid which is a representative of fatty acid. This was analyzed in the present study using lipid labeling method through mass spectrometry.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3364-z) contains supplementary material, which is available to authorized users.

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Delineation of key regulatory elements identifies points of vulnerability in the mitogen-activated signaling network

Cited by 3 publications

References 55 publications

Defining the Akt1 interactome and its role in regulating the cell cycle

Defining the Akt1 interactome and its role in regulating the cell cycle

A cytokine protein-protein interaction network for identifying key molecules in rheumatoid arthritis

Concurrent interactome and metabolome analysis reveals role of AKT1 in central carbon metabolism

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