Epidermal growth factor receptor neddylation is regulated by a desmosomal-COP9 (constitutive photomorphogenesis 9) signalosome complex
- University of Detroit Mercy, United States
- Northwestern University, United States
Abstract
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.
Article and author information
Author details
Kathleen Janee Green
Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (Postdoctoral Fellowship,F32AR066465)
- Nicole Ann Najor
National Institute of General Medical Sciences (Graduate Student Training Grant,T32GM008061)
- Robert M Harmon
American Heart Association (Predoctoral Fellowship)
- Lauren Veronica Albrecht
- Robert M Harmon
National Institute of Arthritis and Musculoskeletal and Skin Diseases (Research Program Grant,R01 AR041836)
- Kathleen Janee Green
National Institute of Arthritis and Musculoskeletal and Skin Diseases (Research Program Grant,R37 AR043380)
- Kathleen Janee Green
National Cancer Institute (Research Program Grant,R01 CA122151)
- Kathleen Janee Green
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Najor et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Epidermal growth factor receptor neddylation is regulated by a desmosomal-COP9 (constitutive photomorphogenesis 9) signalosome complex
eLife 6:e22599.
https://doi.org/10.7554/eLife.22599
