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Publication

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

eLife | 2017

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.

Pubmed ID: 28891468 RIS Download

Research resources used in this publication

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Associated grants

Agency: NIAMS NIH HHS, United States
Id: F32 AR066465
Agency: NIGMS NIH HHS, United States
Id: T32 GM008061
Agency: NCI NIH HHS, United States
Id: P30 CA060553
Agency: NCI NIH HHS, United States
Id: R01 CA122151
Agency: NIAMS NIH HHS, United States
Id: R01 AR041836
Agency: NIAMS NIH HHS, United States
Id: P30 AR057216
Agency: NIAMS NIH HHS, United States
Id: R37 AR043380

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