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  Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium

Brandt, R., Sell, T., Lüthen, M., Uhlitz, F., Klinger, B., Riemer, P., et al. (2019). Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium. Nature Communications, 10(1): 2919. doi:10.1038/s41467-019-10954-y.

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© The Author(s) 2019

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 Urheber:
Brandt, Raphael , Autor
Sell, Thomas , Autor
Lüthen, Mareen , Autor
Uhlitz, Florian, Autor
Klinger, Bertram, Autor
Riemer, Pamela , Autor
Giesecke-Thiel, Claudia1, Autor           
Schulze, Silvia , Autor
El-Shimy, Ismail Amr , Autor
Kunkel, Desiree, Autor
Fauler, Beatrix2, Autor           
Mielke, Thorsten2, Autor           
Mages, Norbert3, Autor           
Herrmann, Bernhard G.4, Autor           
Sers, Christine , Autor
Blüthgen, Nils , Autor
Morkel, Markus, Autor
Affiliations:
1Flow Cytometry Facility (Head: Claudia Giesecke-Thiel), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3039333              
2Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
3Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
4Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              

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Schlagwörter: Cancer models, Gastrointestinal cancer, Oncogenes, Morphogen signalling, Network topology
 Zusammenfassung: Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRASG12V in mouse intestinal organoids, while transgenic BRAFV600E activates ERK in all cells. Quantitative network modelling from perturbation data reveals that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of ERK in the intestine. Furthermore, we find that oncogenic KRAS, together with β-Catenin, favours expansion of crypt cells with high ERK activity. Our experiments highlight key differences between oncogenic BRAF and KRAS in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.

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Sprache(n): eng - English
 Datum: 2019-07-02
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 10.1038/s41467-019-10954-y
PMID: 31266962
 Art des Abschluß: -

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Titel: Nature Communications
  Kurztitel : Nat. Commun.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: London : Nature Publishing Group
Seiten: - Band / Heft: 10 (1) Artikelnummer: 2919 Start- / Endseite: - Identifikator: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723