Frizzled receptors: gatekeepers of Wnt signaling in development and disease

Abstract

Frizzled (FZD) receptors are a subset of G-protein-coupled receptors (GPCRs), the largest class of human cell surface receptors and a major target of FDA-approved drugs. Activated by Wnt ligands, FZDs regulate key cellular processes such as proliferation, differentiation, and polarity, positioning them at the intersection of developmental biology and disease, including cancer. Despite their significance, FZD signaling remains incompletely understood, particularly in distinguishing receptor-specific roles across canonical and non-canonical Wnt pathways. Challenges include defining ligand-receptor specificity, elucidating signal transduction mechanisms, and understanding the influence of post translational modifications and the cellular context. Structural dynamics, receptor trafficking, and non-canonical signaling contributions also remain areas of active investigation. Recent advances in structural biology, transcriptomics, and functional genomics are beginning to address these gaps, while emerging therapeutic approaches-such as small-molecule modulators and antibodies-highlight the potential of FZDs as drug targets. This review synthesizes current insights into FZD receptor biology, examines ongoing controversies, and outlines promising directions for future research and therapeutic development.

Keywords: DVL; FZD; Wnt; cancer; frizzled receptor; signaling.

FIGURE 1

Frizzle (FZD) receptor family protein domains. (A) The FZD receptor family shares a common set of functional domains critical for Wnt binding and intracellular signal transmission. The extracellular cysteine-rich domain (CRD) confers Wnt ligand specificity. A seven-transmembrane (7TM) domain is shared among G-protein-coupled receptors and transmits Wnt binding through conformational changes. The intracellular C-terminal region includes a PDZ-binding motif and recruits intracellular signaling effectors such as Dishevelled. (B) The linear protein domains of human FZD1-10. Made with Biorender.com.

FIGURE 2

Frizzle regulation of canonical and non-canonical Wnt signaling. In canonical Wnt signaling, Wnt ligand binding to the FZD and LRP5/6 co-receptors triggers DVL binding to FZD C-terminal domain. DVL recruits the β-catenin destruction complex resulting in β-catenin stabilization, nuclear accumulation, and Wnt target gene expression via the TCF/LEF transcription factors. In non-canonical Wnt/PCP signaling, Wnt ligand binding to the FZD and ROR/Ryk co-receptors triggers the formation of FZD-PCP complexes (i.e., Vangl, Prickle, Cels, DVL). DVL leads activation of small Rho GTPases, cytoskeleton remodeling, and c-Jun-mediated gene transcription. Finally in non-canonical Wnt/Ca²⁺signaling, Wnt ligand binding to the FZD and ROR/Ryk co-receptors triggers the formation of FZD. Made with Biorender.com.

FIGURE 3

Modes of FZD receptor regulation. (A) FZD post-translational modifications (PTMs) include glycosylation, phosphorylation, palmitoylation, and ubiquitination. N-linked glycosylation in FZD extracellular domains stabilizes Wnt binding and facilitates FZD protein folding. Phosphorylation of the FZD C-terminal domain, by CK1 or PKC, regulate interactions between FZD and intracellular signal effector proteins and FZD trafficking dynamics. Palmitoylation of FZD intracellular regions promotes membrane retention and sustained signaling at the cell surface. FZD endocytosis, degradation, and subsequent signal termination is regulated by ubiquitin PTMs per the dynamic activity of E3 ubiquitin ligases (ZNRF3 and RNF43) and deubiquitinating enzymes (USP46). (B) The tumor microenvironment (TME) contributes to Wnt ligand bioavailabiliy, FZD receptor localization, and downstream receptor signaling. Extra-cellular matrix (ECM) components bind to Wnt to facilitating ligand presentation and stabilize Wnt-FZD interactions. ECM stiffness regulates FZD receptor clustering and intracellular trafficking to enhance Wnt signaling. The hypoxic tumor microenvironment can stimulate FZD receptor and Wnt ligand overexpression. Growth factors present in the TME synergistically enhance Wnt/FZD signaling to promote tumor growth and metastasis. Fibroblasts and macrophages residing within the TME can secrete Wnt ligands and ECM components to further propagate FZD signaling. (C) Spatiotemporal regulation of FZD is essential for proper FZD expression during tissue development, cell polarity, and signaling dynamics. FZD receptor expression is tightly controlled during development and results in temporal and tissue-specific expression patterns. Within epithelial cells, FZD receptors are located to the apical membrane and mediate planar cell polarity. Aberrant FZD receptor expression and mislocalization of FZD receptors disrupts normal signaling pathways during tumorigenesis. (D) FZD gene transcriptional products are regulated at the genomic and epigenetic levels and are susceptible to alterations in cancer. Developmental transcription factors (SOX2, OCT4, NANOG), the β-catenin/TCF/LEF complex, and HIF1α activate FZD gene transcription. Epigenetically, FZD mRNA abundance is regulated by promoter methylation status, histone acetylation levels, and functional chromatin remodeler complexes. In addition, microRNAs (miR-126 and miR-200) target FZD mRNA for degradation and lncRNAs (MALAT1 and HOTAIR) sponge microRNAs to enhance FZD mRNA availability. Finally, FZD receptors undergo gene amplification (FZD7/10) and loss-of-function mutations (FZD9) in cancer. Made with Biorender.com.