Rnf43, also known as E3 ubiquitin-protein ligase RNF43 or RING-type E3 ubiquitin transferase RNF43, is a crucial negative regulator of the Wnt/β-catenin signaling pathway [3]. It functions as a tumor suppressor by ubiquitinating the Frizzled receptor, targeting it for lysosomal degradation and thus inhibiting Wnt/β-catenin signaling [3]. This regulation is vital for processes like embryonic development and adult stem cell homeostasis, and dysregulation is associated with various diseases, especially cancer [4]. Genetically engineered mouse models are valuable for studying its function.

In a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC), loss of Rnf43 accelerated Kras-mediated neoplasia, decreased survival, and remodeled the tumor immune microenvironment, with changes in macrophage, T and B lymphocyte populations, and immune checkpoint molecule expression [2]. In hepatocyte-specific Rnf43/Znrf3 knockout mice, it led to steatohepatitis, increased unsaturated lipids, defective hepatocyte regeneration, and liver cancer due to a differentiation/proliferation imbalance [1].

In conclusion, Rnf43 plays a key role in regulating the Wnt/β-catenin signaling pathway. Model-based research, especially through gene knockout mouse models, has revealed its significance in diseases such as PDAC and liver cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Belenguer, Germán, Mastrogiovanni, Gianmarco, Pacini, Clare, Koo, Bon-Kyoung, Huch, Meritxell. 2022. RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state. In Nature communications, 13, 334. doi:10.1038/s41467-021-27923-z. https://pubmed.ncbi.nlm.nih.gov/35039505/

2. Hosein, Abdel Nasser, Dangol, Gita, Okumura, Takashi, Woermann, Sonja M, Maitra, Anirban. 2021. Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma. In Gastroenterology, 162, 1303-1318.e18. doi:10.1053/j.gastro.2021.12.273. https://pubmed.ncbi.nlm.nih.gov/34973294/

3. Serra, Stefano, Chetty, Runjan. 2017. Rnf43. In Journal of clinical pathology, 71, 1-6. doi:10.1136/jclinpath-2017-204763. https://pubmed.ncbi.nlm.nih.gov/29018044/

4. Farnhammer, Fiona, Colozza, Gabriele, Kim, Jihoon. 2023. RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane. In International journal of stem cells, 16, 376-384. doi:10.15283/ijsc23070. https://pubmed.ncbi.nlm.nih.gov/37643759/