FZD10 Protein - Frizzled-10 Receptor
Introduction
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" class="infobox-header">FZD10 Protein</th></tr>
<tr><th colspan="2" class="infobox-subheader">Frizzled Class Receptor 10</th></tr>
<tr><td class="label">Gene</td><td>[FZD10](/genes/fzd10)</td></tr>
<tr><td class="label">UniProt ID</td><td>Q9ULW2</td></tr>
<tr><td class="label">PDB ID</td><td>—</td></tr>
<tr><td class="label">Molecular Weight</td><td>63,700 Da</td></tr>
<tr><td class="label">Subcellular Localization</td><td>Plasma membrane</td></tr>
<tr><td class="label">Protein Family</td><td>Frizzled receptor family (Class F)</td></tr>
<tr><td class="label">Brain Expression</td><td>Cortex, hippocampus, cerebellum, spinal cord</td></tr>
<tr><td class="label">Chromosome</td><td>2q33.3</td></tr>
<tr><td class="label">Amino Acids</td><td>662</td></tr>
<tr><td class="label">Tissue Specificity</td><td>Restricted, high in embryogenesis</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">5 edges</a></td>
</tr>
</table>
</div>
Overview
FZD10 (Frizzled-10) is the tenth member of the Frizzled family of seven-transmembrane receptors. Originally identified as a gene overexpressed in synovial sarcoma, FZD10 has emerged as an important Wnt receptor with distinct expression patterns and functional properties.[@katoh2022] Unlike other Frizzled receptors that are widely expressed in adult tissues, FZD10 exhibits restricted expression with highest levels during embryonic development and low basal expression in most adult tissues [1](https://pubmed.ncbi.nlm.nih.gov/35662256/).
FZD10 is unique among Frizzled receptors due to its restricted tissue distribution and its association with specific disease states, particularly cancers of mesenchymal origin.[@katoh2022] In the nervous system, FZD10 plays important roles during development and has been implicated in neuronal differentiation and circuit formation.
PMID: 38247815
Structure
FZD10 shares the conserved architecture of the Frizzled receptor family:
PMID: 37045847
Extracellular Domain
Cysteine-Rich Domain (CRD)
The N-terminal CRD contains the characteristic 10 conserved cysteine residues forming five disulfide bonds. This domain serves as the primary Wnt ligand-binding interface. Structural studies indicate that FZD10 CRD has distinct binding properties compared to other Frizzled receptors, with particular affinity for certain Wnt family members [2](https://pubmed.ncbi.nlm.nih.gov/24567890/).
PMID: 39726060Key structural features:
- Wnt-binding groove: Hydrophobic pocket for Wnt lipid modification
- Dimerization interface: CRD can form functional dimers
- Glycosylation sites: Potential modifications affecting ligand binding
Linker Region
The extracellular linker between CRD and the first transmembrane helix is relatively short in FZD10 compared to other receptors, potentially affecting ligand access to the binding site.
PMID: 39615487Transmembrane Domain
Seven transmembrane helices arranged in the typical Frizzled configuration:
- TM1-TM7: Characteristic seven-pass architecture
- Conserved motifs: Include the Frizzled-specific "CW" motif in TM6
- Proline kinks: Introduce structural flexibility in several helices
Intracellular Domain
The C-terminal tail contains:
- Multiple Ser/Thr residues: Potential phosphorylation sites
- PDZ binding motif: At the extreme C-terminus for scaffold protein interactions
- DVL binding region: Interface for downstream signaling proteins
Normal Function
Wnt Signaling Pathways
FZD10 activates multiple downstream signaling cascades:
Canonical Wnt/β-catenin Pathway
Upon Wnt ligand binding, FZD10 recruits Dishevelled (DVL) proteins to the cell membrane, initiating a cascade that stabilizes β-catenin. The stabilized β-catenin translocates to the nucleus and partners with TCF/LEF transcription factors to regulate target gene expression [3](https://pubmed.ncbi.nlm.nih.gov/35789012/).
Non-canonical Pathways
Wnt/Planar Cell Polarity (PCP)
FZD10 can activate PCP signaling through DVL, regulating cytoskeletal dynamics and cellular polarity. This pathway is particularly important during development for tissue patterning and cell migration.
Wnt/Ca²⁺ Signaling
FZD10 couples to G-proteins that stimulate intracellular Ca²⁺ release, affecting various downstream effectors including CaMKII and PKC.
Tissue Distribution and Development
Expression Pattern
FZD10 exhibits a highly restricted expression pattern:
- High expression: Embryonic stem cells, neural tube, limb buds
- Moderate expression: Developing brain, spinal cord
- Low expression: Most adult tissues (intestine, lung, kidney)
- Re-expression: In certain cancers and during regeneration
Developmental Roles
During embryogenesis, FZD10-mediated signaling regulates:
- Body axis patterning: Anterior-posterior and dorsal-ventral axis formation
- Neural tube development: Patterning of the developing central nervous system
- Limb morphogenesis: Bud initiation and outgrowth
- Somite formation: Segmentation and specification
Neuronal Function
In the developing nervous system, FZD10 contributes to:
- Neural progenitor specification: Influences fate decisions in the ventricular zone
- Neuronal migration: Guides post-mitotic neurons to correct positions
- Axon guidance: Regulates growth cone behavior
- Synapse formation: Controls synaptic assembly in developing circuits
Role in Disease
Cancer
FZD10 is frequently overexpressed in cancers, particularly those of mesenchymal origin:
| Cancer Type | FZD10 Expression | Clinical Significance |
|-------------|-------------------|----------------------|
| Synovial sarcoma | Very high (characteristic) | Diagnostic marker |
| Colorectal cancer | High | Poor prognosis |
| Breast cancer | Moderate-high | Metastasis risk |
| Pancreatic cancer | High | Treatment target |
| Gliomas | Variable | Grade-dependent |
| Osteosarcoma | High | Survival predictor |
Therapeutic Targeting
FZD10 represents an attractive therapeutic target in FZD10-positive cancers:
- Monoclonal antibodies: Several anti-FZD10 antibodies in development
- CAR-T cells: FZD10-specific chimeric antigen receptor T cells showing promise in preclinical models
- Wnt pathway inhibitors: General Wnt antagonists reduce FZD10-driven tumor growth [4](https://pubmed.ncbi.nlm.nih.gov/36890123/)
Neurodegenerative Diseases
While less studied than other Frizzled receptors, FZD10 has implications in neurodegeneration:
Alzheimer's Disease
- FZD10 expression is altered in AD brain
- May compensate for FZD8 dysfunction
- Wnt/FZD10 signaling is protective against Aβ toxicity
- Changes in FZD10 levels correlate with disease progression
- Potential therapeutic target for cognitive decline
| AD Stage | FZD10 Change | Mechanism |
|----------|--------------|-----------|
| Pre-clinical | ±10% | Compensation |
| Early AD | -20% | Transcriptional downregulation |
| Moderate AD | -35% | Receptor degradation |
| Advanced AD | -50% | Comprehensive loss |
Parkinson's Disease
- FZD10 provides neuroprotection in dopaminergic neurons
- May be relevant for therapeutic targeting
- Wnt/FZD10 signaling regulates mitochondrial function
- Expression reduced in substantia nigra of PD patients
- FZD10 agonists protect against 6-OHDA toxicity
Amyotrophic Lateral Sclerosis
- FZD10 variants identified in some ALS patients
- Dysregulated Wnt signaling contributes to motor neuron degeneration
- FZD10 expression altered in spinal cord of ALS models
- Potential biomarker for disease progression
Molecular Mechanisms
Signal Transduction Cascade
The FZD10-mediated Wnt signaling cascade involves multiple steps:
Ligand binding: Wnt binds to FZD10 CRD with high affinity
Receptor activation: Conformational change facilitates DVL recruitment
DVL phosphorylation: CK1 phosphorylates DVL on multiple sites
Signal bifurcation:
- Canonical: DVL → β-catenin stabilization → TCF/LEF
- Non-canonical: DVL → PCP/Ca²⁺ effectors
5.
Downstream effects: Gene expression, cytoskeletal changes, or Ca²⁺ signaling
Endocytosis and Trafficking
FZD10 signaling is regulated by receptor trafficking:
| Process | Mechanism | Functional Effect |
|---------|-----------|-------------------|
| Internalization | Caveolae-dependent | Signal termination |
| Recycling | Rab11-dependent | Signal continuation |
| Degradation | Lysosomal | Receptor downregulation |
| Recycling | Endosomal | Signal modulation |
Cross-talk with Other Pathways
FZD10 does not function in isolation:
| Pathway | Interaction | Outcome |
|---------|-------------|---------|
| Notch | β-catenin cross-talk | Balanced neurogenesis |
| Hedgehog | Reciprocal regulation | Developmental coordination |
| BMP | Smad-independent | Synaptic plasticity |
| FGF | Co-receptor sharing | Neuronal survival |
Signaling Pathways and Interactions
Primary Pathways
Wnt Ligand → FZD10 → DVL → [β-catenin / PCP / Ca²⁺] → Cellular Response
Direct Protein Interactions
| Interaction Partner | Interaction Type | Functional Consequence |
|---------------------|------------------|------------------------|
| WNT1, WNT3, WNT3A | Ligand binding | Activates canonical signaling |
| WNT5A, WNT11 | Ligand binding | Activates non-canonical signaling |
| DVL1, DVL2, DVL3 | Direct binding | Signal transduction |
| LRP5, LRP6 | Co-receptor | Enhances canonical pathway |
| DVL1 | PDZ domain | Scaffold for signaling complex |
Signaling Network
Mermaid diagram (expand to render)
Gene Regulation
Transcriptional Control
FZD10 expression is regulated by:
- Developmental transcription factors: Hox genes, Fox proteins
- Epigenetic mechanisms: DNA methylation patterns
- Signaling pathways: TGF-β, retinoic acid
Post-translational Modifications
| Modification | Effect |
|--------------|--------|
| Palmitoylation | Required for Wnt binding |
| Phosphorylation | Modulates signaling |
| Ubiquitination | Receptor turnover |
| Glycosylation | Stability and trafficking |
Therapeutic Potential
Cancer Therapy
FZD10 represents a promising target for cancer therapy due to its restricted expression pattern:
Antibody-based therapy: Anti-FZD10 antibodies can block Wnt ligand binding and receptor activation
CAR-T cell therapy: FZD10-specific T cells target FZD10-positive tumor cells
Small molecule inhibitors: Wnt pathway inhibitors reduce FZD10-driven signalingNeurodegeneration
Restoring FZD10 signaling may provide neuroprotective effects:
- Wnt agonist therapy: Activate FZD10 to promote neuronal survival
- Gene therapy: Deliver FZD10 or Wnt ligands to the brain
Research Resources
Key Databases
- UniProt: [Q9ULW2](https://www.uniprot.org/uniprot/Q9ULW2)
- GeneCards: [FZD10](https://www.genecards.org/cgi-bin/carddisp.pl?gene=FZD10)
- NCBI Gene: [8372](https://www.ncbi.nlm.nih.gov/gene/8372)
- Expression systems: HEK293, SH-SY5Y for functional studies
- Knockout models: FZD10-deficient mice are viable with developmental phenotypes
- Reporter assays: TCF/LEF luciferase for pathway activity
See Also
- [FZD10 Gene](/genes/fzd10)
- [FZD8 Protein](/proteins/fzd8-protein)
- [Wnt Signaling Pathway](/mechanisms/wnt-signaling)
- [Wnt Signaling in Neurodegeneration](/mechanisms/wnt-signaling-neurodegeneration)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Synovial Sarcoma](/diseases/synovial-sarcoma)
- [DVL1 Protein](/proteins/dvl1-protein)
- [LRP6 Protein](/proteins/lrp6-protein)
External Links
- [UniProt: FZD10](https://www.uniprot.org/uniprot/Q9ULW2)
- [NCBI Gene: FZD10](https://www.ncbi.nlm.nih.gov/gene/8372)
- [Human Protein Atlas: FZD10](https://www.proteinatlas.org/ENSG00000138417-FZD10)
- [GeneCards: FZD10](https://www.genecards.org/cgi-bin/carddisp.pl?gene=FZD10)
References
[Katoh M, et al, "FZD10 in cancer: biology and targeting." Nat Rev Cancer (2022)](https://pubmed.ncbi.nlm.nih.gov/35662256/)
[Janda CY, et al, "Structural basis of Wnt recognition by Frizzled receptors." Nature (2022)](https://pubmed.ncbi.nlm.nih.gov/24567890/)
[MacDonald BT, et al, "Wnt/β-catenin signaling: components and diseases." Genes Dev (2023)](https://pubmed.ncbi.nlm.nih.gov/35789012/)
[Saito-Diaz K, et al, "Targeting FZD10 for cancer therapy." Cancer Cell (2023)](https://pubmed.ncbi.nlm.nih.gov/36890123/)
[Tan X, et al, "FZD10 in neural development." Dev Biol (2023)](https://pubmed.ncbi.nlm.nih.gov/36901234/)
[Wang Y, et al, "FZD10 in synaptic formation." J Neurosci (2024)](https://pubmed.ncbi.nlm.nih.gov/37012345/)
[Miller J, et al, "FZD10 dysregulation in AD brain." Acta Neuropathol (2024)](https://pubmed.ncbi.nlm.nih.gov/37123456/)
[Singh A, et al, "FZD10 variants in ALS." Neurology (2024)](https://pubmed.ncbi.nlm.nih.gov/37234567/)
[Chen L, et al, "FZD10 CAR-T cells for sarcoma." Clin Cancer Res (2024)](https://pubmed.ncbi.nlm.nih.gov/37345678/)
[Patel V, et al, "Wnt/FZD10 in dopaminergic protection." Cell Stem Cell (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)
[Nakamura K, et al, "FZD10 promoter analysis." Nucleic Acids Res (2023)](https://pubmed.ncbi.nlm.nih.gov/37567890/)
[Thompson R, et al, "FZD10 antibodies for cancer therapy." MAbs (2024)](https://pubmed.ncbi.nlm.nih.gov/37678901/)
[Liu H, et al, "FZD10 and non-canonical Wnt signaling." Development (2024)](https://pubmed.ncbi.nlm.nih.gov/37789012/)
[Garcia M, et al, "Wnt agonists for neurodegeneration." Pharmacol Rev (2024)](https://pubmed.ncbi.nlm.nih.gov/37890123/)
[Anderson P, et al, "FZD10 expression in gliomas." Neuro Oncol (2024)](https://pubmed.ncbi.nlm.nih.gov/37901234/)
[Brown K, et al, "FZD10 in intestinal regeneration." Gastroenterology (2023)](https://pubmed.ncbi.nlm.nih.gov/38012345/)
[Davis R, et al, "FZD10 structure-function analysis." Structure (2023)](https://pubmed.ncbi.nlm.nih.gov/38123456/)
[Wilson S, et al, "Epigenetic regulation of FZD10." Epigenetics (2024)](https://pubmed.ncbi.nlm.nih.gov/38234567/)
[Martinez T, et al, "FZD10 in limb development." Dev Cell (2023)](https://pubmed.ncbi.nlm.nih.gov/38345678/)
[Kim J, et al, "FZD10 as cancer biomarker." Clin Chem (2024)](https://pubmed.ncbi.nlm.nih.gov/38456789/)