Epidermal Growth Factor Receptor neddylation is regulated by a desmosomal-COP9 (Constitutive Photomorphogenesis 9) signalosome complex.

Elife 2017 09 11;6. Epub 2017 Sep 11.

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, United States.

Cell junctions are scaffolds that integrate mechanical and chemical signaling. We previously showed that a desmosomal cadherin promotes keratinocyte differentiation in an adhesion-independent manner by dampening Epidermal Growth Factor Receptor (EGFR) activity. Here we identify a potential mechanism by which desmosomes assist the de-neddylating COP9 signalosome (CSN) in attenuating EGFR through an association between the Cops3 subunit of the CSN and desmosomal components, Desmoglein1 (Dsg1) and Desmoplakin (Dp), to promote epidermal differentiation. Silencing CSN or desmosome components shifts the balance of EGFR modifications from ubiquitination to neddylation, inhibiting EGFR dynamics in response to an acute ligand stimulus. A reciprocal relationship between loss of Dsg1 and neddylated EGFR was observed in a carcinoma model, consistent with a role in sustaining EGFR activity during tumor progression. Identification of this previously unrecognized function of the CSN in regulating EGFR neddylation has broad-reaching implications for understanding how homeostasis is achieved in regenerating epithelia.

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http://dx.doi.org/10.7554/eLife.22599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663478PMC
September 2017
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(Supplied by CrossRef)
Desmosome regulation and signaling in disease
Broussard et al.
Cell and Tissue Research 2015
Chapter Six - The Ubiquitin Network in the Control of EGFR Endocytosis and Signaling
Conte et al.
Progress in Molecular Biology and Translational Science 2016

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