ZNRF3

Last update 08 May 2025

Basic Info

Synonyms

BK747E2.3, E3 ubiquitin-protein ligase ZNRF3, FLJ22057

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Introduction

E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby restricting the size of the intestinal stem cell zone (PubMed:22575959). Along with RSPO2 and RNF43, constitutes a master switch that governs limb specification (By similarity).

100 Clinical Results associated with ZNRF3

100 Translational Medicine associated with ZNRF3

0 Patents (Medical) associated with ZNRF3

181

Literatures (Medical) associated with ZNRF3

07 Apr 2025·Oncogene

Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels

Article

Author: van Merode, Jenna ; de Schipper, Nicky ; Smits, Ron ; van de Kamp, Lisa ; Neves Cabrita, Madalena ; Peppelenbosch, Maikel P ; Zhang, Ruyi ; Massaar, Sanne ; Niu, Jiahui ; Li, Shanshan

AbstractZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through which mechanisms they contribute to cancer. Here we show that all truncating mutations analyzed at endogenous levels exhibit loss-of-function, with longer variants retaining partial activity. Regarding missense mutations, we show that 27/82 ZNRF3 variants in the RING and R-Spondin domain structures, lead to (partial) loss-of-function/hyperactivation. Mechanistically, defective R-Spondin domain variants appear to undergo endoplasmic-reticulum-associated degradation due to protein misfolding, leading to reduced protein levels. They fail to reach the membrane correctly, which can be partially restored for several variants by culturing cells at 27 °C. Although RING and R-Spondin domain mutations in RNF43/ZNRF3 are often considered to possess dominant-negative oncogene-like activity in cancers, our findings challenge this notion. When representative variants are heterozygously introduced into endogenous ZNRF3, their impact on β-catenin signaling mirrors that of heterozygous knockout, suggesting that the supposed dominant-negative effect is non-existent. In other words, so-called “hyperactivating” ZNRF3/RNF43 mutations behave as classical loss-of-function mutations at endogenous levels.

17 Jan 2025·ACS Chemical Biology

2-Cyanopyrimidine-Containing Molecules for N-Terminal Selective Cyclization of Phage-Displayed Peptides

Article

Author: Coleman, Demonta D. ; Das, Sukant ; Cherif, Moulay I. ; Liu, Wenshe Ray ; Hampton, J. Trae ; Dobie, Connor R.

Current methods for the macrocyclization of phage-displayed peptides often rely on small molecule linkers that nonspecifically react with targeted amino acid residues. To expand tool kits for more regioselective macrocyclization of phage-displayed peptides, this study explores the unique condensation reaction between an N-terminal cysteine and nitrile along with the reactivity of an internal cysteine. Five 2-cyanopyrimidine derivatives were synthesized for this purpose and evaluated for their selective macrocyclization of a protein-fused model peptide. Among these, two novel linkers, 2-chloro-N-(2-cyanopyrimidin-5-yl)acetamide (pCAmCP) and 2-chloro-N-(2-cyanopyrimidin-4-yl)acetamide (mCAmCP), emerged as efficient molecules and were demonstrated to macrocyclize phage-displayed peptide libraries flanked by an N-terminal and an internal cysteine. Using these linkers to generate macrocyclic peptide libraries displayed on phages, peptide ligands for the ZNRF3 extracellular domain were successfully identified. One of the identified peptides, Z27S1, exhibited potent binding to ZNRF3 with a K_D value of 360 nM. Notably, the selection results revealed distinct peptide enrichment patterns depending on whether mCAmCP or pCAmCP was used, underscoring the significant impact of linker choice on macrocyclic peptide identification. Overall, this study validates the development of two novel regioselective, small molecule linkers for phage display of macrocyclic peptides and highlights the benefits of employing multiple linkers during phage selections.

31 Dec 2024·mAbs

Coactivation of Tie2 and Wnt signaling using an antibody–R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia

Article

Author: Park, Jong-Gil ; Cho, Young-Lai ; Min, Jeong-Ki ; Lee, Dong Gwang ; Jeon, Min-Young ; Jang, Ju-Hong ; Noh, Ji-Hun ; Yang, Wonjun ; Lee, Jangwook ; Lee, Nam-Kyung ; Hwang, Byungtae

Therapeutic angiogenesis by intentional formation of blood vessels is essential for treating various ischemic diseases, including limb ischemia. Because Wnt/β-catenin and angiopoietin-1/Tie2 signaling play important roles in endothelial survival and vascular stability, coactivation of these signaling pathways can potentially achieve therapeutic angiogenesis. In this study, we developed a bifunctional antibody fusion, consisting of a Tie2-agonistic antibody and the Furin domains of R-spondin 3 (RSPO3), to simultaneously activate Tie2 and Wnt/β-catenin signaling. We identified a Tie2-agonistic antibody T11 that cross-reacted with the extracellular domain of human and mouse Tie2, and evaluated its ability to increase endothelial cell survival and tube formation. We generated a bifunctional T11-RF12 by fusing T11 with the Furin-1 and -2 domains of RSPO3. T11-RF12 could bind not only to Tie2, but also to LGR5 and ZNRF3, which are counterparts of the Furin-1 and -2 domains. T11-RF12 significantly increased Wnt/β-catenin signaling, as well as the formation of capillary-like endothelial tubes, regardless of the presence of Wnt ligands. Coactivation of Tie2 and Wnt/β-catenin signaling by T11-RF12 increased the blood flow, and thereby reduced foot necrosis in a mouse hindlimb ischemia model. In particular, T11-RF12 induced therapeutic angiogenesis by promoting vessel stabilization through pericyte coverage and retaining endothelial expression of Frizzled 10 and active β-catenin. These results indicate that the agonistic synergism of Tie2 and Wnt/β-catenin signaling achieved using T11-RF12 is a novel therapeutic option with potential for treating limb ischemia and other ischemic diseases.

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ZNRF3

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