PamgeneAnalyzeR: open and reproducible pipeline for kinase profiling

Bekkar, Amel; Nasrallah, Anita; Guex, Nicolas; Fajas, Lluís; Xénarios, Ioannis; López-Mejía, Isabel C.

doi:10.1093/bioinformatics/btz858

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…Kinase Statistics indicates the overall change of the peptide set that represents the kinase. Kinase statistics value <0 indicates lower kinase activity in the compound spiked lysate and vice versa ( 32 , 33 ). Table 5 lists the 20 most changed kinases within treated HL60 cell lysates by 0.1 μM 4e , ranked according to their Kinase Score.…”

Section: Resultsmentioning

confidence: 99%

SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases

et al. 2022

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Tirbanibulin (KX2-391, KX-01), a dual non-ATP (substrate site) Src kinase and tubulin-polymerization inhibitor, demonstrated a universal anti-cancer activity for variety of cancer types. The notion that KX2-391 is a highly selective Src kinase inhibitor have been challenged by recent reports on the activities of this drug against FLT3-ITD mutations in some leukemic cell lines. Therefore, we hypothesized that analogues of KX2-391 may inhibit oncogenic kinases other than Src. A set of 4-aroylaminophenyl-N-benzylacetamides were synthesized and found to be more active against leukemia cell lines compared to solid tumor cell lines. N-(4-(2-(benzylamino)-2-oxoethyl)phenyl)-4-chlorobenzamide (4e) exhibited activities at IC50 0.96 µM, 1.62 µM, 1.90 µM and 4.23 µM against NB4, HL60, MV4-11 and K562 leukemia cell lines, respectively. We found that underlying mechanisms of 4e did not include tubulin polymerization or Src inhibition. Such results interestingly suggested that scaffold-hopping of KX2-391 may change the two main underlying cytotoxic mechanisms (Src and tubulin). Kinase profiling using two methods revealed that 4e significantly reduces the activities of some other potent oncogenic kinases like the MAPK member ERK1/2 (>99%) and it also greatly upregulates the pro-apoptotic c-Jun kinase (84%). This research also underscores the importance of thorough investigation of total kinase activities as part of the structure-activity relationship studies.

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Section: Resultsmentioning

confidence: 99%

SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases

et al. 2022

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“…In this study, we investigated the influence of pneumococcal H 2 O 2 on the protein kinase activity of the H441 human lung epithelial cell line, a generally accepted model of alveolar epithelial cells ( 22 ). The effects of H 2 O 2 released by Spn during infection on the (de-) activation status of the global kinome were investigated using a peptide-based kinase activity assay (PamStation platform), which enables identification of differentially activated kinases based on the phosphorylation of immobilized substrate peptides in infected lung cells ( 23 ). In our approach, we compared the kinomes of H441 cells infected with either Spn wild type ( SpnWT ) or Spn Δ lctO Δ spxB mutant, the latter of which lacks LctO and SpxB and is therefore strongly attenuated in H 2 O 2 production (generates only 3% of SpnWT H 2 O 2 levels) ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Pneumococcal hydrogen peroxide regulates host cell kinase activity

Bazant,

Weiss,

Baldauf

et al. 2024

Front. Immunol.

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IntroductionProtein kinases are indispensable reversible molecular switches that adapt and control protein functions during cellular processes requiring rapid responses to internal and external events. Bacterial infections can affect kinase-mediated phosphorylation events, with consequences for both innate and adaptive immunity, through regulation of antigen presentation, pathogen recognition, cell invasiveness and phagocytosis. Streptococcus pneumoniae (Spn), a human respiratory tract pathogen and a major cause of community-acquired pneumoniae, affects phosphorylation-based signalling of several kinases, but the pneumococcal mediator(s) involved in this process remain elusive. In this study, we investigated the influence of pneumococcal H2O2 on the protein kinase activity of the human lung epithelial H441 cell line, a generally accepted model of alveolar epithelial cells.MethodsWe performed kinome analysis using PamGene microarray chips and protein analysis in Western blotting in H441 lung cells infected with Spn wild type (SpnWT) or with SpnΔlctOΔspxB -a deletion mutant strongly attenuated in H2O2 production- to assess the impact of pneumococcal hydrogen peroxide (H2O2) on global protein kinase activity profiles.ResultsOur kinome analysis provides direct evidence that kinase activity profiles in infected H441 cells significantly vary according to the levels of pneumococcal H2O2. A large number of kinases in H441 cells infected with SpnWT are significantly downregulated, whereas this no longer occurs in cells infected with the mutant SpnΔlctOΔspxB strain, which lacks H2O2. In particular, we describe for the first time H2O2-mediated downregulation of Protein kinase B (Akt1) and activation of lymphocyte-specific tyrosine protein kinase (Lck) via H2O2-mediated phosphorylation.

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“…One of these analytic tools is the Kinomics Toolkit, which gives users a platform for exploration of the peptide phosphorylation data but does not provide upstream kinase predictions [ 10 ]. Another tool that was designed specifically to process kinase array data is the PamgeneAnalyzeR package, though this package is primarily focused on the pre-processing steps of kinase array datasets and not the downstream analysis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

KRSA: An R package and R Shiny web application for an end-to-end upstream kinase analysis of kinome array data

et al. 2021

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Phosphorylation by serine-threonine and tyrosine kinases is critical for determining protein function. Array-based platforms for measuring reporter peptide signal levels allow for differential phosphorylation analysis between conditions for distinct active kinases. Peptide array technologies like the PamStation12 from PamGene allow for generating high-throughput, multi-dimensional, and complex functional proteomics data. As the adoption rate of such technologies increases, there is an imperative need for software tools that streamline the process of analyzing such data. We present Kinome Random Sampling Analyzer (KRSA), an R package and R Shiny web-application for analyzing kinome array data to help users better understand the patterns of functional proteomics in complex biological systems. KRSA is an All-In-One tool that reads, formats, fits models, analyzes, and visualizes PamStation12 kinome data. While the underlying algorithm has been experimentally validated in previous publications, we demonstrate KRSA workflow on dorsolateral prefrontal cortex (DLPFC) in male (n = 3) and female (n = 3) subjects to identify differential phosphorylation signatures and upstream kinase activity. Kinase activity differences between males and females were compared to a previously published kinome dataset (11 female and 7 male subjects) which showed similar global phosphorylation signals patterns.

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PamgeneAnalyzeR: open and reproducible pipeline for kinase profiling

Cited by 6 publications

References 10 publications

SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases

SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases

Pneumococcal hydrogen peroxide regulates host cell kinase activity

KRSA: An R package and R Shiny web application for an end-to-end upstream kinase analysis of kinome array data

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