TY - JOUR
T1 - Epidermal growth factor receptor neddylation is regulated by a desmosomal-COP9 (Constitutive photomorphogenesis 9) signalosome complex
AU - Najor, Nicole Ann
AU - Fitz, Gillian Nicole
AU - Koetsier, Jennifer Leigh
AU - Godsel, Lisa Marie
AU - Albrecht, Lauren Veronica
AU - Harmon, Robert
AU - Green, Kathleen Janee
N1 - Funding Information:
The authors would like to thank all the members of the Green Laboratory, Cory Simpson, M.D., Ph. D., Robert Lavker, Ph.D., and Spiro Getsios, Ph.D. for insightful discussions during development of this project and comments on the manuscript. Gift antibodies were provided by Julie Segre (K1, K10, Loricrin). Keratinocytes were obtained from the Keratinocyte Core of the Northwestern University Skin Disease Research Center, and histological analysis (H and E staining) was conducted by the Pathology Core of the Northwestern Skin Disease Research Center Chicago, IL, USA, with support from the National Institute of Arthritis And Musculoskeletal And Skin Diseases of the National Institute of Health (NIAMS/NIH) (P30AR057216). Nikon SIM imaging was performed at the Northwestern University Cell Imaging Facility supported by the National Cancer Institute of the National Institute of Health (NCI/NIH) grant CCSG P30 CA060553 (Robert H Lurie Comprehensive Cancer Center). This work was supported by NIAMS/NIH (R01 AR041836 and R37 AR043380, with partial support from R01 CA122151). NA Najor was supported by a Kirschstein postdoctoral fellowship (F32AR066465). LV Albrecht was supported by a Kirschstein predoctoral fellowship (T32GM008061), by the Malkin Scholar Program from the Robert H Lurie Comprehensive Cancer Center of North-western University, and an American Heart Association predoctoral fellowship. RM Harmon was supported by a Kirschstein predoctoral fellowship (T32GM008061) and an American Heart Association predoctoral fellowship. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the Northwestern University Skin Disease Research Center, NIAMS/NIH, or NCI/NIH.
Publisher Copyright:
© Najor et al.
PY - 2017/9/11
Y1 - 2017/9/11
N2 - 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.
AB - 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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U2 - 10.7554/eLife.22599
DO - 10.7554/eLife.22599
M3 - Article
C2 - 28891468
AN - SCOPUS:85032994780
VL - 6
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e22599
ER -