Abstract
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.
Highlights
Terms of use This work is brought to you by the University of Southern Denmark
casitas B-lineage lymphoma (Cbl)-b is Recruited to the pY15 of Cylindromatosis Tumor Suppressor Protein (CYLD)—Taking into account that phosphorylated tyrosine residues often act as docking sites for the interaction with SH2- or PTB domaincontaining proteins [47], we investigated a potential ability of CYLD pY15 to recruit molecular effectors belonging to the epidermal growth factor (EGF) pathway
The activities of the Cbl proteins constitute an essential pillar for the negative regulation of receptor tyrosine kinases (RTKs) pathways and defective binding of these E3 ligases with the EGF receptor (EGFR) promotes a compromised ubiquitination and degradation of the receptor [56]
Summary
Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. CYLD facilitates the interaction of EGFR with Cbl-b through its Tyr 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. The binding of a ligand, such as Epidermal Growth Factor (EGF), promotes the dimerization of the receptor and the subsequent activation of its kinase activity, which further leads to the autophosphorylation of tyrosine residues on the intracellular region of the EGFR [1, 2] These modified residues act as docking sites for recruiting SH2 or PTB domain- containing signaling proteins [3, 4], the stimulation triggers the association of large intracellular complexes that support rapid spread and amplification of the signal, eventually resulting in a specific cellular output [5]
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