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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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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5614-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-DC1D-5
Genre: Journal Article

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 Creators:
Brandt, Raphael , Author
Sell, Thomas , Author
Lüthen, Mareen , Author
Uhlitz, Florian, Author
Klinger, Bertram, Author
Riemer, Pamela , Author
Giesecke-Thiel, Claudia1, Author              
Schulze, Silvia , Author
El-Shimy, Ismail Amr , Author
Kunkel, Desiree, Author
Fauler, Beatrix2, Author              
Mielke, Thorsten2, Author              
Mages, Norbert3, Author              
Herrmann, Bernhard G.4, Author              
Sers, Christine , Author
Blüthgen, Nils , Author
Morkel, Markus, Author
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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Free keywords: Cancer models, Gastrointestinal cancer, Oncogenes, Morphogen signalling, Network topology
 Abstract: 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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Language(s): eng - English
 Dates: 2019-07-02
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41467-019-10954-y
PMID: 31266962
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 10 (1) Sequence Number: 2919 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723