MassIVE MSV000080803

Imported Reanalysis Dataset Public PXD002460

Context-dependent regulatory mechanisms control site-specific information processing within the MEK/ERK module

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Description

The impact of the cellular context and receptor type on the dynamics of phosphorylation cycles in signaling pathways are unclear. We employ an unbiased approach to identify network alterations that explain phosphorylation dynamics of the MEK/ERK module in response to hepatocyte growth factor or interleukin-6, comparing primary hepatocytes with the immortalized cell line HaCaT. By combining quantitative mass spectrometry with dynamic modeling, we elucidate the network structure in primary hepatocytes. For HaCaT, our model predicts additional dual feedback regulation, which we experimentally identify as DUSP6 and paxillin. Model analyses reveal switch-like ERK phospho-form distribution profiles in primary hepatocytes that are severely altered in HaCaT, explaining threshold, sensitivity and saturation behavior. We apply our approach to human hepatocellular carcinoma samples and identify, as predicted, elevated threonine-phosphorylated ERK levels in the tumor. This suggests that the prevalence of the mono-phosphorylated ERK rather than the doubly phosphorylated ERK is indicative for dysregulated proliferation. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Phosphorylation ; Systems biology ; Mass spectrometry ; Signal transduction ; Cellular information processing

Contact

Principal Investigators:
(in alphabetical order) 		Marcel Schilling, German Cancer Research Center (DKFZ) Systems Biology of Signal Transduction Im Neuenheimer Feld 280 69120 Heidelberg Germany, N/A
Submitting User: ccms

Publications

Iwamoto N, D'Alessandro LA, Depner S, Hahn B, Kramer BA, Lucarelli P, Vlasov A, Stepath M, Böhm ME, Deharde D, Damm G, Seehofer D, Lehmann WD, Klingmüller U, Schilling M.
Context-specific flow through the MEK/ERK module produces cell- and ligand-specific patterns of ERK single and double phosphorylation.
Sci Signal. 2016 Feb 2;9(413):ra13. Epub 2016 Mar 2.

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