FZD10

FZD10 is a Frizzled-family seven-transmembrane receptor that transduces canonical Wnt/β-catenin signaling in development and disease. FZD10 binds Wnt ligands (Wnt7b, Wnt1) at the cell surface and cooperates with LRP5/LRP6 co-receptors to activate β-catenin-dependent transcription, while selectively coupling to Gα13 to co-activate YAP/TAZ transcriptional programs (PMID:15923619, PMID:28126591, PMID:32531778). FZD10 expression is regulated epigenetically through BRMS1L/HDAC1-mediated H3K9 deacetylation at its promoter and post-transcriptionally through METTL3-, FTO-, and ALKBH5-dependent m6A modification of its mRNA, which controls mRNA stability and feeds back via a β-catenin/c-Jun/METTL3 positive loop to sustain Wnt signaling in cancer stem cells (PMID:25406648, PMID:30967398, PMID:36764493). FZD10 protein and mRNA are also packaged into tumor-derived exosomes and transferred intercellularly, where they activate ERK1/2 and PI3K signaling to promote proliferation and angiogenesis in recipient cells (PMID:31349740, PMID:34671555).

1. 2005 High

   Establishing FZD10 as a bona fide Wnt receptor resolved which Frizzled family members mediate canonical signaling: Wnt7b directly binds FZD10 on the cell surface and activates β-catenin signaling specifically in the presence of LRP5, ruling out noncanonical pathway activation through this receptor.

   Evidence Cell surface binding assays and canonical versus noncanonical reporter assays in transfected cells

   PMID:15923619

   Open questions at the time

   • Structural basis of the Wnt7b–FZD10 interaction not determined
   • Whether FZD10 has ligand preferences beyond Wnt7b was not systematically tested
   • Downstream signaling intermediates between FZD10-LRP5 and β-catenin stabilization not mapped
2. 2008 Medium

   Demonstrating that a monoclonal antibody against native FZD10 is efficiently internalized upon binding confirmed that FZD10 resides on the cell surface and undergoes ligand/antibody-induced endocytosis, relevant to its signaling regulation and therapeutic targeting.

   Evidence Cell binding assay, internalization assay, and in vivo fluorescent imaging of labeled anti-FZD10 MAb in synovial sarcoma cells

   PMID:18271942

   Open questions at the time

   • Whether internalization is clathrin- or caveolae-dependent was not addressed
   • The fate of internalized FZD10 (recycling vs. degradation) was not tracked
3. 2014 High

   Identifying BRMS1L/HDAC1-mediated H3K9 deacetylation as a silencing mechanism at the FZD10 promoter revealed how epigenetic regulation of receptor expression controls Wnt/β-catenin output and metastatic behavior in breast cancer.

   Evidence ChIP for HDAC1 and H3K9 marks at FZD10 promoter, BRMS1L RNAi, FZD10 rescue, and in vivo xenograft metastasis assay

   PMID:25406648

   Open questions at the time

   • Whether other histone marks or DNA methylation co-regulate FZD10 at this locus was not examined
   • Tissue specificity of BRMS1L–FZD10 regulation not explored beyond breast cancer
4. 2017 High

   Mapping FZD10's selective coupling to Gα13 (excluding Gα12, Gαi1, GαoA, Gαs, Gαq) and showing Wnt-induced Gα13 dissociation with downstream YAP/TAZ activation established FZD10 as a G protein-coupled receptor with a defined heterotrimeric G protein selectivity profile.

   Evidence G protein interaction panel, dynamic mass redistribution measurements, and YAP/TAZ reporter assays

   PMID:28126591

   Open questions at the time

   • Structural determinants within FZD10 that confer Gα13 selectivity are unknown
   • How Gα13 signaling converges on YAP/TAZ versus β-catenin downstream of FZD10 is not delineated
5. 2019 High

   Discovery that m6A modification of FZD10 mRNA by FTO and ALKBH5 stabilizes the transcript and upregulates Wnt/β-catenin signaling revealed an epitranscriptomic layer of FZD10 regulation with functional consequences for PARP inhibitor resistance.

   Evidence m6A-seq, mRNA stability assays, FTO/ALKBH5 knockdown, pathway reporters, and in vivo xenograft validation in BRCA-mutated ovarian cancer cells

   PMID:30967398

   Open questions at the time

   • Specific m6A reader proteins that recognize FZD10 mRNA were not identified
   • Whether m6A-dependent FZD10 regulation operates in normal physiology remains untested
6. 2019 Medium

   Demonstrating that FZD10 protein and mRNA are packaged into exosomes and that exosomal transfer rescues proliferation in FZD10-depleted cancer cells established a paracrine mode of FZD10 signaling beyond canonical ligand–receptor interaction.

   Evidence Exosome isolation, FZD10 siRNA silencing, and exosome transfer/rescue assays in colorectal, gastric, hepatic, and cholangio cancer cells

   PMID:31349740

   Open questions at the time

   • Mechanism of FZD10 sorting into exosomes is unknown
   • Whether exosomal FZD10 signals via the same β-catenin pathway as membrane-resident FZD10 was not tested
   • No in vivo validation of exosomal FZD10 transfer
7. 2020 Medium

   In vivo loss- and gain-of-function studies in Xenopus/chick showed FZD10 is required for Wnt1-dependent dorsal neural tube patterning and that excess FZD10 inhibits Wnt1 in the absence of LRP6, extending FZD10's developmental role and co-receptor dependence to neural patterning.

   Evidence Morpholino knockdown and overexpression with Wnt1/Wnt3a/LRP6 epistasis in Xenopus and chick spinal cord

   PMID:32531778

   Open questions at the time

   • Whether FZD10 functions redundantly with other Frizzled receptors in neural tube patterning not resolved
   • Downstream transcriptional targets in neural progenitors not identified
8. 2021 Medium

   Placing FZD10 upstream of the ERK1/2/Ki-67 proliferative axis via exosome transfer experiments defined a non-canonical signaling output for exosomal FZD10 distinct from its established β-catenin role.

   Evidence FZD10 siRNA silencing and exosome rescue with pERK1/2 and Ki-67 readouts in colorectal and gastric cancer cells

   PMID:34671555

   Open questions at the time

   • Direct interaction between FZD10 and ERK1/2 pathway components not demonstrated
   • Whether ERK1/2 activation by exosomal FZD10 requires LRP co-receptors is unknown
9. 2023 High

   Identifying a METTL3–m6A–FZD10–β-catenin/c-Jun positive feedback loop in liver cancer stem cells unified the epitranscriptomic and transcriptional regulation of FZD10, showing that FZD10-driven β-catenin/c-Jun transcriptionally activates METTL3, which in turn m6A-methylates FZD10 mRNA to sustain self-renewal and drug resistance.

   Evidence RIP, luciferase reporters, patient-derived tumor organoids and xenografts in hepatocellular carcinoma

   PMID:36764493

   Open questions at the time

   • Whether the METTL3–FZD10 feedback loop operates in non-hepatic cancers is unknown
   • Which m6A reader(s) mediate the stabilization of FZD10 mRNA downstream of METTL3 not identified
10. 2023 Medium

    Validation of miR-26b-3p as a direct negative regulator of FZD10, with FZD10 loss increasing GSK3β phosphorylation and decreasing β-catenin to promote enteric glial cell apoptosis, connected microRNA-mediated FZD10 regulation to a non-cancer physiological context (intestinal motility).

    Evidence Luciferase reporter validation, FZD10 siRNA, flow cytometry, GSK3β/β-catenin Western blot, in vivo mouse model

    PMID:37728849

    Open questions at the time

    • Other miRNAs targeting FZD10 not systematically surveyed
    • Whether miR-26b-3p–FZD10 axis operates in intestinal stem cells is unknown

• The structural basis of FZD10's selectivity for Gα13 over other Gα subunits, the identity of m6A readers that stabilize FZD10 mRNA, and the mechanism by which FZD10 is sorted into exosomes remain unresolved.
• No crystal or cryo-EM structure of FZD10 in complex with Gα13 or Wnt ligand
• m6A reader proteins acting on FZD10 mRNA not identified
• Mechanism of FZD10 sorting into exosomes completely undefined
• Relative contribution of β-catenin vs. YAP/TAZ arms downstream of FZD10 in different tissues not quantified