| Symbol |
DDR2 |
| Full Name |
Discoidin Domain Receptor 2 |
| Aliases |
TKT, NTRKR3, DDR2 |
| Chromosome |
1q23.3 |
| NCBI Gene |
4921 |
| Ensembl |
ENSG00000137337 |
| UniProt |
Q16832 |
| Diseases |
[Parkinson's Disease](/diseases/parkinsons-disease) |
| Expression |
Brain, cartilage, bone, lung, kidney |
¶ DDR2 — Discoidin Domain Receptor 2
DDR2 (Discoidin Domain Receptor 2) is a receptor tyrosine kinase that functions as a collagen sensor and regulates cellular responses including survival, proliferation, migration, and matrix remodeling. Originally identified as a collagen receptor on fibroblasts and epithelial cells, DDR2 is expressed in neurons and glial cells where it plays important roles in brain homeostasis. Genetic variants in DDR2 have been associated with an increased risk of Parkinson's disease through genome-wide association studies.
¶ Gene and Protein Structure
DDR2 is a single-pass transmembrane receptor with the following architecture:
- Extracellular domain: Contains a DS (discoidin) domain that binds collagen
- Transmembrane helix: Single-pass membrane-spanning region
- Cytoplasmic tyrosine kinase domain: Belongs to the insulin receptor superfamily
The DDR2 gene is located on chromosome 1q23.3 and encodes a 896-amino acid protein. Unlike most receptor tyrosine kinases, DDR2 is activated by collagen binding rather than classical growth factors, and its activation kinetics are slow (hours) compared to rapid growth factor receptors (minutes).
DDR2 serves as the primary receptor for fibrillar collagen types I, II, and III. Collagen binding induces DDR2 autophosphorylation and downstream signaling through:
- MAPK pathway: ERK1/2 and p38 activation
- PI3K/AKT pathway: Pro-survival signaling
- STAT pathway: Transcriptional regulation
In the central nervous system, DDR2 is expressed in neurons and participates in:
- Neuronal survival: AKT-mediated pro-survival signaling in response to collagen
- Synaptic organization: Regulates postsynaptic structure and function
- Axonal guidance: Modulates neurite outgrowth during development
- Neuroprotection: Buffers against various insults including oxidative stress
In glial cells, DDR2 mediates:
- Astrocyte activation: Response to CNS injury and remodeling
- Microglial modulation: Regulation of inflammatory responses
- Oligodendrocyte function: Myelin maintenance
Large-scale genome-wide association studies have identified DDR2 variants as risk factors for Parkinson's disease. The mechanism involves:
- Altered collagen-DDR2 signaling in the brain
- Impaired clearance of alpha-synuclein
- Dysregulated neuronal survival pathways
Research demonstrates that DDR2 modulates alpha-synuclein aggregation and toxicity:
- DDR2 activation promotes autophagy-mediated clearance of alpha-synuclein aggregates
- Loss of DDR2 function leads to accumulation of toxic oligomers
- DDR2 deficiency exacerbates neurodegeneration in PD models
DDR2 provides neuroprotection through multiple mechanisms:
- AKT pathway activation: Pro-survival signaling in dopaminergic neurons
- Autophagy enhancement: Facilitates clearance of protein aggregates
- Collagen-mediated signaling: Brain extracellular matrix remodeling
- Anti-inflammatory effects: Modulates microglial activation
flowchart TD
A["DDR2 Activation<br/>(Collagen Binding)"] --> B["Receptor<br/>Autophosphorylation"]
B --> C["AKT/mTOR<br/>Signaling"]
B --> D["MAPK/ERK<br/>Signaling"]
B --> E["Autophagy<br/>Induction"]
C --> F["Neuronal<br/>Survival"]
D --> G["Synaptic<br/>Maintenance"]
E --> H["Alpha-Synuclein<br/>Clearance"]
I["DDR2 Variants<br/>(PD Risk)"] --> J["Impaired<br/>Collagen Signaling"]
J --> K["Reduced<br/>AKT Activity"]
K --> L["Reduced<br/>Autophagy"]
L --> M["Alpha-Synuclein<br/>Accumulation"]
M --> N["Neurodegeneration"]
H -.-> N
F -.-> N
classDef blue fill:#e1f5fe,stroke:#333
classDef green fill:#c8e6c9,stroke:#333
classDef red fill:#ffcdd2,stroke:#333
classDef purple fill:#f3e5f5,stroke:#333
click A "/genes/ddr2" "DDR2 Gene"
click C "/mechanisms/akt-signaling-pathway" "AKT Signaling"
click E "/mechanisms/autophagy-pathway" "Autophagy Pathway"
click H "/mechanisms/synucleinopathy" "Synucleinopathy"
click I "/diseases/parkinsons-disease" "Parkinson's Disease"
Modulating DDR2 activity represents a potential therapeutic strategy for PD:
- DDR2 agonists: Could enhance neuronal survival and alpha-synuclein clearance
- DDR2 modulators: Small molecules that enhance collagen-receptor signaling
- DDR2 has complex roles in peripheral tissues (cartilage, bone)
- Systemic DDR2 modulation may have side effects
- BBB penetration required for CNS-targeted approaches
Mouse models with DDR2 deficiency show:
- Increased alpha-synuclein aggregation
- Accelerated neurodegeneration
- Impaired motor function
These phenotypes are rescued by DDR2 overexpression or agonist treatment.
DDR2 interacts with several other Parkinson's disease-linked genes and pathways:
- LRRK2: Both modulate autophagy and vesicular trafficking
- GBA1: Both affect lysosomal function and alpha-synuclein clearance
- SNCA: Direct protein-protein interaction and regulatory relationship
- PARK2 (Parkin): Shared pathways in mitophagy and protein clearance
Key open questions include:
- What are the specific collagen types that activate DDR2 in the brain?
- How do DDR2 variants influence PD risk at the molecular level?
- Can DDR2 agonism provide therapeutic benefit in established PD?
- What is the relationship between DDR2 and other PD risk genes?