Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor

Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the t...

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Published in:Molecular & cellular proteomics 2017-08, Vol.16 (8), p.1433-1446
Main Authors: Sanchez-Quiles, Virginia, Akimov, Vyacheslav, Osinalde, Nerea, Francavilla, Chiara, Puglia, Michele, Barrio-Hernandez, Inigo, Kratchmarova, Irina, Olsen, Jesper V., Blagoev, Blagoy
Format: Article
Language:English
Subjects:
Cascades
Cbl protein
Cbl-b protein
Chromatography, Liquid
Degradation
Deubiquitinating Enzyme CYLD - genetics
Deubiquitinating Enzyme CYLD - metabolism
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - metabolism
HeLa Cells
Homeostasis
Humans
Immunofluorescence
Mass spectrometry
Mass spectroscopy
NF-κB protein
Phosphorylation
Proteolysis
Proteomics
Proto-Oncogene Proteins c-cbl - metabolism
Recruitment
Signal transduction
Signaling
Tandem Mass Spectrometry
Tumor suppressor genes
Tumor suppressor proteins
Tumors
Tyrosine
Tyrosine - metabolism
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary:Cylindromatosis tumor suppressor protein (CYLD) is a deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine-phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr15 phosphorylation in response to EGF, which leads to fine-tuning of the receptor's ubiquitination and subsequent degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors suppressor for the negative regulation of a tumorigenic signaling pathway.
ISSN:1535-9476
1535-9484
DOI:10.1074/mcp.M116.066423