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Phospho-proteomic characterization of CCDC6-RET

ABSTRACT: Here we show that a CCDC6-RET fusion product, a driver and therapeutic target in lung and thyroid cancers, is a highly active dimeric kinase in solution. Time-resolved mass spectrometry analysis together with a robust biochemical and biophysical characterization reveal the autophosphorylation kinetics and nucleotide dependency. Structural analyses together with cross-linking mass spectrometry data provided clear insights into the mechanism of autoactivation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Marta Isasa

PROVIDER: PXD053907 | Pride | 2026-04-27

REPOSITORIES: Pride

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			Action	DRS
	20190211_EF_IP_PTC1_0min_1_20190211173545.raw	Raw
	20190211_EF_IP_PTC1_0min_2.raw	Raw
	20190211_EF_IP_PTC1_30min_1.raw	Raw
	20190211_EF_IP_PTC1_30min_2.raw	Raw
	20200915_JS_Ivan_PTC1_9_0min.raw	Raw

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Publications

The oncogenic CCDC6-RET fusion protein is a dual ATP- and ADP-dependent kinase.

Martín-Hurtado Ana A Contreras Julia J Sánchez-Wandelmer Jana J Zarzuela Eduardo E García Fernando F Le Coq Johanne J Boskovic Jasminka J Muñoz Inés G IG Gago Federico F Muñoz Javier J Isasa Marta M Plaza-Menacho Iván I

Nature communications 20260306 1

Gene fusion products involving protein kinases are known drivers in human cancers and actionable targets for personalized therapy, yet the structural and molecular determinants that control their function are largely unexplored. Here we show that a CCDC6-RET fusion protein, a driver and therapeutic target in lung and thyroid cancers, is a highly active dimeric kinase. Time-resolved mass spectrometry together with a robust biochemical and biophysical characterization reveal that CCDC6-RET functio ...[more]

PMID: 41792117

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Peroxiredoxin 2 is required for the exercise induced redox mediated adaptation to exercise

Project description:During exercise there is a site-specific increase in ROS within muscle required for the beneficial adaptive response by activation of specific signalling pathways. Peroxiredoxin 2 (Prdx2), an abundant cytoplasmic 2-Cys peroxidase, is required for the adaptive beneficial hormesis response to H2O2, myoblasts with knockdown of Prdx2 did not increase mitochondrial content and had disrupted myogenesis. Using a 5-day swimming protocol in C. elegans, previously been demonstrated to improve healthspan, we observed increased mitochondrial content, fitness, survival and longevity in wild type (N2) worms. However, prdx-2 mutant worms had decreased fitness, disrupted mitochondria, reduced survival and lifespan following exercise. Global proteomics following exercise revealed an increase in the abundance of proteins involved in fatty oxidation and ion transport, decrease in proteins involved in cuticle formation in N2 worms. In the prdx-2 mutants following exercise there was an increase in proteins related to the mTOR pathway and decrease in transsulfuration and microRNA biogenesis proteins. Relative quantification of the reversible oxidation state of individual Cysteine (Cys) residues revealed an increased oxidation of specific Cys residues following exercise in prdx-2 mutant. A number of regulatory Cys residues of metabolic, cytoskeletal and calcium handling proteins are reduced in N2 worms. A redox signalling relay whereby the oxidative equivalents from ROS are transferred from evolutionary conserved Prdxs to target proteins, would confer specificity on redox signalling required for the beneficial adaptations to exercise.

2023-03-11 | PXD037698 | Pride

Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice

Project description:Nucleolar stress (NS) kills cells by p53-dependent and independent manners. To investigate the mechanisms of p53-indendendent toxicity, we here used (PR)n arginine-rich peptides as inducers of NS, which are found in patients of some neurodegenerative diseases. Although these peptides generate NS, how this translates to toxicity is poorly understood. We here reveal that whereas (PR)n expression leads to an overall decrease in protein abundance for the majority of the proteome, this occurs concomitant to an accumulation of free ribosomal proteins in the cytoplasm, which is a hallmark of ribosomopathies. Conversely, cells with acquired resistance to (PR)n peptides present a global downregulation of ribosomal proteins and low levels of mTOR signaling. In mice, systemic expression of (PR)97 drives widespread NS and accelerated ageing, associated to an increased expression of ribosomal proteins and mTOR hyperactivation. Furthermore, the progeroid phenotype of (PR)97-expressing mice is alleviated by rapamycin. Importantly, we show that the generalized accumulation of free ribosomal proteins is not restricted to (PR)n peptides, but is a common outcome in response to chemical or genetic perturbations that generate NS such as Actinomycin D, TIF-IA depletion or the expression or mutant HMGB1 forms recently associated to rare human diseases. Together, our study provides in vivo evidence for the role of NS as a driver of ageing in mammals, and describes a general model to understand the mechanisms behind p53-independent cell toxicity caused by NS.

2024-03-11 | PXD043752 | Pride

Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice

2024-03-08 | PXD046380 | Pride

Targeting mitochondrial translation overcomes multidrug resistance in FBXW7-deficient cells

Project description:FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.

2022-06-08 | PXD029981 | Pride

Transcription profiling of Vitis vinifera cv. Malbec after exposure to UV-B radiation

Project description:In the present study we have used a new custom made Affymetrix GrapeGen GeneChip to investigate gene expression responses of grapevine cultivar Malbec to one dose of biologically effective UV-B radiation (4.75 kJ m-2 d-1), administered at two different intensities (16 h, to 8.25 µW cm-2 or 4 h, to 33 µW cm2 UV-B).

2010-12-21 | E-MEXP-2541 | biostudies-arrayexpress

Senescent cells display an altered immunopeptidome and promote CD8-dependent antitumor immunity

Project description:Cellular senescence is a stress response known to activate innate immunity. However, how senescent cells interact with the adaptive immune system remains largely unexplored. Here, we show that senescent cells display an enhanced MHC class I antigen processing and presentation. Furthermore, senescent cells present an altered immunopeptidome including unique non-mutated antigens that can be recognized by specific CD8 T cells. Immunization of mice with senescent cancer cells triggers strong protective CD8-dependent antitumor responses, superior to immunogenic cell death. Similarly, induction of senescence in human primary cancer cells hyperactivates their cognate reactive CD8 T cell. Our study indicates that immunization with senescent cells provides a sustained source of antigens that strongly activate anti-tumor CD8 T cells.

2022-10-18 | PXD033714 | Pride

RNA-seq analysis of the fungal mycelium of the plant pathogen Pyricularia oryzae treated with and antimicrobial peptide analog of a Trichoderma peptaibol

Project description:We aimed at investigating the mode of action of an antimicrobial peptide analog of a Trichoderma peptaibol. Conidia of P. oryzae (IT10 strain) were cultured in Complete Medium at a final concentration of 2x105 conidia per mL for 3 days at 30 °C under shaking at 150 rpm. After three days, 50 µM of the Peptide 4rink were added to samples containing actively growing mycelium. Untreated samples were used as control. Three h after peptide treatment, fungal mycelia were collected, filtered with 100 µm Cell Strainer (Corning®), rinsed with sterile water and stored at -80 °C for RNA extraction. Total RNA was extracted with the RNeasy Plant Mini kit (Qiagen) following the manufacturer’s instructions, performing the DNase digestion directly on the column. The integrity and concentration of the RNA samples were checked with Qubit fluorimeter and Bioanalyzer. RNA samples with RIN values < 7 were discarded. Four biological replicates of each treatment were submitted to RNA sequencing and analysis at CRIBI Biotechnology Center (University of Padova). Two µg of total RNA were subjected to PolyA tail capture and rRNA depletion for selection of mRNA. Directional (stranded) RNA libraries were prepared, quantified and subjected to quality control. Sequencing was performed on Illumina Nova Seq 6000 platform. Twenty million reads were produced for each sample and checked for quality control. Based on our RNA-seq data, the molecular mechanisms of the fungicidal activity of these peptide analogs appear to be related to their ability to cause cell wall and membrane damages and to induce autophagic cell death in fungal cells. This is the first transcriptomic analysis on a fungus treated with peptaibol analogs.

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Effect of an immune challenge and feed supplements on broiler chicken individual breast muscle protein synthesis

Project description:Optimization of broiler chicken breast muscle protein accretion is key for the efficient production of poultry meat, whose demand is steadily increasing. In a context where antimicrobial growth promoters use is being restricted, it is important to find alternatives as well as to characterize the effect of immunological stress on broiler chicken growth. Despite of its importance, research on broiler chicken muscle protein dynamics has been mostly limited to the study of mixed protein turnover. The present study aims to characterize the effect of a bacterial challenge and the feed supplementation of a citrus and a cucumber extract on broiler chicken individual breast muscle proteins fractional synthesis rates (FSR) using a recently developed dynamic proteomics pipeline. 21 day-old broiler chickens were administered a single 2H2O dose before being culled at different timepoints. A total of 60 breast muscle protein extracts from five experimental groups (Unchallenged, Challenged, Control Diet, Diet 1 and Diet 2) were analyzed using a DDA proteomics approach. Proteomics data was filtered in order to reliably calculate multiple proteins FSR making use of a newly developed bioinformatics pipeline. Broiler breast muscle proteins FSR uniformly decreased following a bacterial challenge, this change was judged significant for 15 individual proteins, the two major functional clusters identified as well as for mixed breast muscle protein. Citrus or cucumber extract feed supplementation did not show any effect on the breast muscle protein FSR of immunologically challenged broilers. The present study has identified potential predictive markers of breast muscle growth and provided new information on broiler chicken breast muscle protein turnover which could be essential for improving the efficiency of broiler chicken meat production.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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