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Epidermal growth factor receptor neddylation is regulated by a desmosomal-COP9 (constitutive photomorphogenesis 9) signalosome complex

  1. Nicole Ann Najor
  2. Gillian Nicole Fitz
  3. Jennifer Leigh Koetsier
  4. Lisa Mary Godsel
  5. Lauren Veronica Albrecht
  6. Robert M Harmon
  7. Kathleen Janee Green Is a corresponding author
  1. University of Detroit Mercy, United States
  2. Northwestern University, United States
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Cite as: eLife 2017;6:e22599 doi: 10.7554/eLife.22599

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

  1. Nicole Ann Najor

    Department of Biology, School of Engineering and Science, University of Detroit Mercy, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Gillian Nicole Fitz

    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jennifer Leigh Koetsier

    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lisa Mary Godsel

    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lauren Veronica Albrecht

    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Robert M Harmon

    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kathleen Janee Green

    Department of Pathology, Feinberg School of Medicine, Northwestern University, Detroit, United States
    For correspondence
    kgreen@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-7332-5867

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.

Reviewing Editor

  1. Reinhard Fässler, Reviewing Editor, Max Planck Institute of Biochemistry, Germany

Publication history

  1. Received: October 22, 2016
  2. Accepted: September 8, 2017
  3. Accepted Manuscript published: September 11, 2017 (version 1)

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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