Proteomics

Dataset Information

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INKA, an integrative analysis pipeline for inference of hyperactive phosphokinases in mass spectrometry-based phosphoproteomics data


ABSTRACT: As a large proportion of current targeted cancer therapies is based on specific (tyrosine) kinase inhibitors, uncovering the identity of hyperactive kinases at work in tumors is crucial for proper treatment selection. A major challenge in phosphoproteomic data analysis is to relate kinases to the extent and magnitude of their phosphorylation 'footprint', and to rank them accordingly in order to single out kinases that are crucial for tumor growth in individual patients. Previous approaches have either zeroed in on phosphorylation of kinases themselves as a read-out of kinase activity, or focused on inferring kinase activities from the phosphorylation of their (supposed) substrates. Here, we combine both kinase-centric and substrate-centric analyses. We present a computational pipeline called Integrative Inferred Kinase Activity (INKA) scoring that integrates the observed abundance of phosphopeptides derived from (i) kinases as a whole, (ii) their kinase activation loop segments, (iii) proteins deduced to be kinase substrates based on prior experimental knowledge of kinase-substrate relationships, and/or (iv) kinase substrates predicted by the sequence motif- and network-based NetworKIN algorithm. As a proof of concept, applying this pipeline to the analysis of phosphoproteomic data on seven different oncogene-driven cancer cell lines highlighted the high, top ranking inferred activity of known driver kinases in these cells. This demonstrates the potential of label-free MS-based phosphoproteomics combined with dedicated data analysis for identifying (hyper)active kinases that, in potential future applications to tumors, may be selected for targeted inhibition in a personalized treatment setting.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Epithelial Cell

SUBMITTER: Sander Piersma  

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD006616 | Pride | 2019-04-18

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
MaxQuant_TiOx_data.zip Other
MaxQuant_pTyr_HCC827_ER3.zip Other
MaxQuant_pTyr_HCC827parental.zip Other
MaxQuant_pTyr_K562_H2228_SK_Mel28.zip Other
QE1_140414_OPL1013_IdR_CvA_pTyrIP_A.raw Raw
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Publications


Identifying hyperactive kinases in cancer is crucial for individualized treatment with specific inhibitors. Kinase activity can be discerned from global protein phosphorylation profiles obtained with mass spectrometry-based phosphoproteomics. A major challenge is to relate such profiles to specific hyperactive kinases fueling growth/progression of <i>individual</i> tumors. Hitherto, the focus has been on phosphorylation of either kinases or their substrates. Here, we combined label-free kinase-c  ...[more]

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