Abstract
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area. Membrane E3 ligase ZNRF3 and RNF43 are critical negative feedback regulators of the Wnt pathway, which function through promoting ubiquitination and degradation of Wnt receptors. R-spondin proteins (RSPO1-4) serve as natural antagonists of ZNRF3/RNF43. To maintain strong and sustained Wnt/β-catenin signaling, cancers need to overcome ZNRF3/RNF43-mediated feedback inhibition. Indeed, mutations of RNF43/ZNRF3 and recurrent translocations of RSPO2/RSPO3 have recently been identified in various cancers. Significantly, genetic alterations in RNF43/ZNRF3/RSPO2/RSPO3 have shown promise as predictive biomarkers in pre-clinical models for the efficacy of upstream Wnt inhibitors. In this review, we will discuss the biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module, and their value as biomarkers to identify Wnt-addicted tumors.
Highlights
The evolutionarily conserved Wnt signaling pathway plays critical roles in embryonic development and adult tissue homeostasis in all multicellular animals [1]
These results suggest that DVL serves as an adaptor protein targeting ZNRF3/RNF43 to FZD to promote FZD ubiquitination and degradation
The regulation of Wnt receptor turnover by the RSPO-ZNRF3/RNF43 signaling module has emerged as a key regulatory mechanism of Wnt signaling
Summary
The evolutionarily conserved Wnt signaling pathway plays critical roles in embryonic development and adult tissue homeostasis in all multicellular animals [1]. Wnt proteins are secreted lipoglycoprotein ligands that control cell proliferation, migration, cell fate specification, and polarity formation. The canonical Wnt signaling cascade drives specific gene expression programs through regulating the stability of transcription cofactor β-catenin. Wnt proteins can activate the β-catenin–independent Plana Cell Polarity (PCP) pathway to coordinate cell and tissue movements. The Frizzled (FZD) family of seven transmembrane-domain proteins serves as the core receptors of. Wnt proteins, and they are required for both Wnt/β-catenin and Wnt/PCP signaling. Wnt proteins utilize different coreceptors to activate different downstream signaling pathways; Wnt proteins bind to coreceptor LRP5/6 to turn on the Wnt/β-catenin pathway, and they bind to coreceptor ROR1/2, RYK or PTK7 to initiate the Wnt/PCP pathway. Aberrant Wnt signaling is associated with various diseases including cancer
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