G protein-coupled receptors (GPCRs) have a substantial role in tumorigenesis and are described as a "cancer driver". Aberrant expression or activation of GPCRs leads to the deregulation of downstream signaling pathways, thereby promoting cancer progression. In hepatocellular carcinoma (HCC), the Wnt signaling pathway is frequently activated and it is associated with an aggressive HCC phenotype. Frizzled (FZD) receptors, a family member of GPCRs, are known to mediate Wnt signaling. Accumulating findings have revealed the deregulation of FZD receptors in HCC and their functional roles have been implicated in HCC progression. Given the important role of FZD receptors in HCC, we summarize here the expression pattern of FZD receptors in HCC and their corresponding functional roles during HCC progression. We also further review and highlight the potential targeting of FZD receptors as an alternative therapeutic strategy in HCC.
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http://dx.doi.org/10.3390/ijms19010313 | DOI Listing |
J Med Chem
December 2024
Section of Receptor Biology & Signaling, Dept. Physiology & Pharmacology, Karolinska Institutet, Stockholm S-171 77, Sweden.
The Frizzled family (FZD) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD for cancer treatment.
View Article and Find Full Text PDFDev Cell
November 2024
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:
The rapidly regenerating intestinal epithelium requires crypt intestinal stem cells (ISCs). Wnt/β-catenin signaling maintains crypt homeostasis and Lgr5+ ISCs, and WNT ligands bind Frizzled receptors (FZD1-10). Identifying specific FZD(s) essential for intestinal homeostasis has been elusive; however, bioengineered antagonists blocking Wnt binding to FZD5 and FZD8 deplete the gut epithelium in vivo, highlighting potential roles.
View Article and Find Full Text PDFbioRxiv
October 2024
Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956.
Wnt signaling is essential for both the development and homeostasis of diverse cellular lineages, including hematopoietic stem cells. Organism-wide, Wnt signals are tightly regulated, as overactivation of the pathway can lead to tumorigenesis. Although numerous Wnt ligands and Frizzled (Fzd) receptors exist, how particular Wnt/Fzd pairings are established and how their signals are regulated is poorly understood.
View Article and Find Full Text PDFChem Commun (Camb)
November 2024
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
We synthesized a WNT5A β-hairpin peptide responsible for the protein's binding to its receptor, Frizzled. Full affinity to Frizzled requires all three disulfides but not an invariant tryptophan that significantly contributes to the buried surface area. Our work opens the avenue to target the Wnt-Fzd interface using synthetic peptides.
View Article and Find Full Text PDFbioRxiv
October 2024
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins.
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