Dataset Information

Kinase activity ranking (KAR) quantifies the contribution of protein kinases to the regulation of cell viability

ABSTRACT: New method to determine kinase activity based on phosphoproteomics data

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Permanent Cell Line Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Pedro Casado-Izquierdo

LAB HEAD: Pedro Casado Izquierdo

PROVIDER: PXD005073 | Pride | 2017-07-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	F020761.dat-pride.xml-merged.pride.mgf.gz	Mgf
	F020761.dat-pride.xml-merged.pride.mztab.gz	Mztab
	F020761.dat-pride.xml-merged.xml.gz	Xml
	F021200.dat-pride.xml-merged.pride.mgf.gz	Mgf
	F021200.dat-pride.xml-merged.pride.mztab.gz	Mztab

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Publications

Kinase activity ranking using phosphoproteomics data (KARP) quantifies the contribution of protein kinases to the regulation of cell viability.

Wilkes Edmund H EH Casado Pedro P Rajeeve Vinothini V Cutillas Pedro R PR

Molecular & cellular proteomics : MCP 20170703 9

Cell survival is regulated by a signaling network driven by the activity of protein kinases; however, determining the contribution that each kinase in the network makes to such regulation remains challenging. Here, we report a computational approach that uses mass spectrometry-based phosphoproteomics data to rank protein kinases based on their contribution to cell regulation. We found that the scores returned by this algorithm, which we have termed kinase activity ranking using phosphoproteomics ...[more]

PMID: 28674151

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Project description:Poly(ADP-ribose) Polymerase 1 (PARP-1) is a nuclear enzyme that catalyse the transfer of ADP-ribose units from NAD+ to several target proteins involved in cellular stress responses. Using the cell line WRL68, we have previously shown that the activation of PARP-1 induced by oxidative stress after H2O2 treatment lead to depletion of cellular NAD+ and ATP, which promote cell death. In this work, we used LC-MS/MS based phosphoproteomics to show that the oxidative damage induced by H2O2 treatment modified the phosphorylation of several proteins in WRL68 cells, most of them related to transcription process. Interestingly, genetic or pharmacological inhibition of PARP-1 reduced the phosphorylation of YAP1, a transcriptional coactivator involved in cell survival, in WRL68 cells after H2O2 treatment. Inhibition of PARP-1 increased cell viability after oxidative treatment and diminished the degradation of YAP1; the elimination of YAP1 by gene silencing abrogated the protective effect of PARP-1 inhibition, indicating that YAP1 is important for the survival of WRL68 cells after oxidative damage. In the same way, the supplementation of NAD+, substrate of PARP-1, on WRL68 cells suffering oxidative damage reduced the phosphorylation of YAP1, suggesting that the loss of cellular NAD+ caused by PARP-1 activation after oxidative treatment is responsible for the phosphorylation of YAP1. Finally, PARP-1 silencing after oxidative treatment diminished the activation of AMPK, a master regulator of cell metabolism implicated in the restoration of energy balance during metabolic stress. Since NAD+ supplementation reduced the phosphorylation of some AMPK substrates in WRL68 cells after oxidative treatment, we hypothesize that the loss of cellular NAD+ after PARP-1 activation may induce a metabolic stress that activates AMPK. In summary, we showed a new crucial role of PARP-1 in the response to oxidative stress in WRL68 cells; PARP-1 activation reduces the cell viability by promoting the phosphorylation and degradation of YAP1, which is mediated by the energy stress caused by PARP-1 activation.