RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy

Abstract

RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have a worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

“…Of note, we found no correlation of response with the presence of APC or CTNNB1 mutations or β-catenin protein expression or localization in mCRC BRAF-V600E tumors (Extended Data Fig. 9a–d and Supplementary Table 1 ), suggesting that noncanonical WNT pathways 34 , 35 , rather than canonical (β-catenin-dependent) signaling, might be involved in modulation of anti-BRAF/EGFR activity.…”

WNT signaling and cancer stemness

“…Genetic alterations in WNT signaling molecules drive carcinogenesis in colorectal, gastric, liver, uterine and other cancers [ 6 ]. Loss-of-function alterations in the APC (adenomatous polyposis coli), AXIN1 and AXIN2 genes and gain-of-function mutations in the CTNNB1 (β-catenin) gene activate the canonical WNT signaling cascade owing to stabilization and nuclear accumulation of β-catenin [ 7 ], while loss-of-function alterations in the RNF43 (ring finger protein 43) gene can activate both canonical and noncanonical WNT signaling cascades through stabilization of plasma membrane Frizzled, LRP6 and ROR1 [ 8 ].…”

Vangl as a Master Scaffold for Wnt/Planar Cell Polarity Signaling in Development and Disease

“…For example, in melanoma cells, Vangl1 and Vangl2 interact with the E3 ubiquitin ligase RNF43. In this context, Vangl2 colocalizes with RNF43 at the plasma membrane and undergoes RNF43-mediated ubiquitination that results in Vangl2 proteasomal degradation and inhibition of Wnt5a-mediated cell invasion ( Radaszkiewicz et al, 2021 ). We ( Wald et al, 2017 ) and others ( Sun et al, 2017 ) have implicated Vangl as a scaffold for the E3 ubiquitin ligase Nrdp1, and have identified that the coiled-coil domain of Nrdp1 is critical for interaction with Vangl1 and Vangl2 ( Wald et al, 2017 ).…”