High-Throughput Assessment of Kinome-Wide Activation States

Schmidlin, Thierry; Rontogianni, Stamatia; Gelder, Charlotte A. G. H. van; Stecker, Kelly E.; Eshof, Bart L. van den; Kemper, Kristel; Lips, Esther H.; Biggelaar, Maartje van den; Peeper, Daniel S.; Heck, Albert J. R.; Altelaar, A.F. Maarten

doi:10.2139/ssrn.3275288

Cited by 16 publications

(23 citation statements)

References 50 publications

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“…P values were corrected for multiple hypothesis testing using the Benjamini-Hochberg procedure. For additional insight into kinase activity, we visualized enrichment of kinase activation loops phosphorylation, calculated by a rank sum test, of loops taken from a curated list from Schmidlin et al (2019); in addition we visualized enrichment of phosphorylation of kinase substrate sets from the PTM-SEA analysis (Krug et al, 2019). Multi-omics clustering Non-negative matrix factorization (NMF) implemented in the NMF R-package (Gaujoux and Seoighe, 2010) was used to perform unsupervised clustering of tumor samples and to identify proteogenomic features (proteins, phosphosites, acetylsites, RNA transcripts and somatic copy number alterations) that showed characteristic abundance patterns for each cluster.…”

Section: Kinase Phosphorylation Outliersmentioning

confidence: 99%

Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Krug

Jaehnig

Satpathy

et al. 2020

Cell

333

334

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SUMMARY The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this “proteogenomics” approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases.Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.

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Section: Kinase Phosphorylation Outliersmentioning

confidence: 99%

Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Krug

Jaehnig

Satpathy

et al. 2020

Cell

333

334

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“…The SRM assay was developed using previous described methods 72,98 . The assay was developed on a TSQ Altis (Thermo Scientific) and a TSQ Vantage (Thermo Scientific).…”

Section: Srm Assay Developmentmentioning

confidence: 99%

Temporal Quantitative Proteomics of mGluR-induced Protein Translation and Phosphorylation in Neurons

Gelder

Penning

Veth

et al. 2020

Molecular & Cellular Proteomics

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At neuronal synapses, activation of group I metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-induced signaling pathways, we integrated quantitative phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy in cultured hippocampal neurons stimulated with DHPG, a specific agonist for group I mGluRs. We identified several kinases with important roles in DHPG-induced mGluR activation, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation were identified, whereby Intersectin-1 was validated as a novel player in this pathway. This study revealed several new insights into the molecular pathways downstream of group I mGluR activation in hippocampal neurons, and provides a rich resource for further analyses.

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“…The activation loop (A-loop) is a well-conserved region inside the kinase domain whose phosphorylation is necessary for kinase activation (Adams, 2003; Ahiri, 2019). Thus, phosphosite intensity level of the A-loop can be used as a proxy for kinase activity quantification (Walley et al, 2013; Beekhof et al, 2019; Schmidlin et al, 2019). First, we performed a whole-proteome Arabidopsis in-silico A-loop prediction and were able to identify the region on 1,360 proteins (Supplementary Data Set 8a).…”

Section: Resultsmentioning

confidence: 99%

Interplay between brassinosteroids and TORC signaling in Arabidopsis revealed by integrated multi-dimensional analysis

Montes

Liao

Nolan

et al. 2021

Preprint

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Brassinosteroids (BR) and Target of Rapamycin Complex (TORC) are two major processes coordinating plant growth and stress responses. BRs function through a signaling pathway to extensively regulate gene expression and TORC is known to regulate translation and autophagy. Recent studies revealed that these two pathways crosstalk, but a system-wide view of their interplay is still missing. Thus, we performed transcriptome, proteome, and phosphoproteome profiling of Arabidopsis mutants with altered levels of either BIN2 or RAPTOR1B, two key players in BR and TORC signaling, respectively. We found that perturbation of BIN2 or RAPTOR1B levels affects a common set of gene-products involved in growth and stress responses. Additionally, we performed Multiplexed Assay for Kinase Specificity (MAKS), which provided a system-wide view of direct BIN2 substrates. Furthermore, phosphoproteomic data was used to reconstruct a kinase-signaling network and to identify novel proteins dependent on BR and/or TORC signaling pathways. Loss of function mutants of many of these proteins led to an altered BR response and/or modulated autophagy activity. Altogether, these results provide genome-wide evidence for crosstalk between BR and TORC signaling and established a kinase signaling network that defines the molecular mechanisms of BR and TORC interactions in the regulation of plant growth/stress balance.

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High-Throughput Assessment of Kinome-Wide Activation States

Cited by 16 publications

References 50 publications

Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Temporal Quantitative Proteomics of mGluR-induced Protein Translation and Phosphorylation in Neurons

Interplay between brassinosteroids and TORC signaling in Arabidopsis revealed by integrated multi-dimensional analysis

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