{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRNF43 is a transmembrane RING‐type E3 ubiquitin ligase that plays a pivotal role in negatively regulating Wnt signaling. It acts by ubiquitinating key Wnt receptors such as the Frizzled family members, thereby promoting their internalization and degradation. In addition, RNF43 interacts with secreted agonists (for example, the R‐spondin proteins) and intracellular adaptor proteins such as Dishevelled to modulate both canonical and noncanonical Wnt pathways. Importantly, RNF43 not only controls receptor turnover at the plasma membrane but in some contexts also affects downstream nuclear events, fine‐tuning the stem cell and developmental programs driven by Wnt signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, RNF43 frequently emerges as a tumor suppressor whose genetic inactivation—often by truncating frameshift or deleterious missense mutations—disrupts its inhibitory influence on Wnt signaling. Such mutations have been identified in colorectal, pancreatic, endometrial, ovarian, and gastric tumors and are strongly associated with aberrant Wnt pathway activation, expansion of cancer stem cell populations, and progression along distinct molecular subtypes (for example, microsatellite instability or BRAF-mutant cancers). RNF43 mutation status has also been shown to serve as a predictive biomarker for therapeutic responses, as its loss of function can confer sensitivity to targeted agents such as Wnt pathway inhibitors or PI3K/mTOR antagonists."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical function in Wnt receptor regulation, RNF43 influences other cellular processes that contribute to tumor biology. Several studies have revealed roles for RNF43 in modulating p53-dependent apoptotic pathways, cell-cycle regulation, and even noncanonical Wnt signaling through interactions with diverse molecular partners. Post-translational modifications—such as phosphorylation within conserved serine clusters—are critical for its regulatory activity, and in vivo models have underscored its impact on tissue homeostasis, regeneration, and tumorigenesis. Furthermore, alterations in RNF43 expression and function are increasingly being exploited as prognostic indicators and as potential therapeutic targets in cancers where its mutation or downregulation is linked to aggressive behavior and altered drug responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "47"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bon-Kyoung Koo, Maureen Spit, Ingrid Jordens, et al. 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