Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β-catenin by the ubiquitin-proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)-associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP-dependent manner. Ubiquitination of Evi involves the E2-conjugating enzyme UBE2J2 and the E3-ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD-dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

Original publication

DOI

10.15252/embj.201797311

Type

Journal article

Journal

Embo j

Publication Date

15/02/2018

Volume

37

Keywords

CGRRF1, Evi/Wls/GPR177, Porcn, Wnt signaling, regulatory ERAD, Acyltransferases, Adenocarcinoma, Cells, Cultured, Colon, Colonic Neoplasms, Endoplasmic Reticulum-Associated Degradation, Gene Expression Regulation, Humans, Membrane Proteins, Signal Transduction, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitination, Valosin Containing Protein, Wnt Proteins