DDR2 — Discoidin Domain Receptor 2
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DDR2 — Discoidin Domain Receptor 2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>DDR2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Discoidin Domain Receptor 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>TKT, NTRKR3, DDR2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q23.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4921" target="_blank">4921</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137337" target="_blank">ENSG00000137337</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q16832" target="_blank">Q16832</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain, cartilage, bone, lung, kidney</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
DDR2 — Discoidin Domain Receptor 2
Overview
...DDR2 — Discoidin Domain Receptor 2
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">DDR2 — Discoidin Domain Receptor 2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>DDR2</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Discoidin Domain Receptor 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>TKT, NTRKR3, DDR2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q23.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4921" target="_blank">4921</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137337" target="_blank">ENSG00000137337</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q16832" target="_blank">Q16832</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain, cartilage, bone, lung, kidney</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
DDR2 — Discoidin Domain Receptor 2
Overview
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](/diseases/parkinsons-disease) through genome-wide association studies[@iwaki2022].
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).
Normal Function
Collagen Signaling
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
Neuronal Functions
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
Glial Functions
In glial cells, DDR2 mediates:
- Astrocyte activation: Response to CNS injury and remodeling
- Microglial modulation: Regulation of inflammatory responses
- Oligodendrocyte function: Myelin maintenance
Role in Parkinson's Disease
Genetic Association
Large-scale genome-wide association studies have identified DDR2 variants as risk factors for [Parkinson's disease](/diseases/parkinsons-disease)[@iwaki2022]. The mechanism involves:
- Altered collagen-DDR2 signaling in the brain
- Impaired clearance of [alpha-synuclein](/genes/snca)
- Dysregulated neuronal survival pathways
Alpha-Synuclein Interaction
Research demonstrates that DDR2 modulates [alpha-synuclein](/genes/snca) aggregation and toxicity[@sivananthan2023]:
- 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
Neuroprotective Mechanisms
DDR2 provides neuroprotection through multiple mechanisms[@chen2021]:
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 activationMechanistic Pathways
Mermaid diagram (expand to render)
Therapeutic Implications
DDR2 as a Target
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
Challenges
- DDR2 has complex roles in peripheral tissues (cartilage, bone)
- Systemic DDR2 modulation may have side effects
- BBB penetration required for CNS-targeted approaches
Preclinical Evidence
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.
Relationship to Other PD Genes
DDR2 interacts with several other Parkinson's disease-linked genes and pathways:
- [LRRK2](/genes/lrrk2): Both modulate autophagy and vesicular trafficking
- [GBA1](/genes/gba1): Both affect lysosomal function and alpha-synuclein clearance
- [SNCA](/genes/snca): Direct protein-protein interaction and regulatory relationship
- [PARK2 (Parkin)](/genes/park2): Shared pathways in mitophagy and protein clearance
Research Directions
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?See Also
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alpha-Synuclein](/genes/snca)
- [LRRK2 Gene](/genes/lrrk2)
- [GBA1 Gene](/genes/gba1)
- [PARK2 (Parkin) Gene](/genes/park2)
- [Autophagy Pathway](/mechanisms/autophagy-pathway)
- [AKT Signaling Pathway](/mechanisms/akt-signaling-pathway)
External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/4921](https://www.ncbi.nlm.nih.gov/gene/4921)
- Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137337](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000137337)
- UniProt: [https://www.uniprot.org/uniprot/Q16832](https://www.uniprot.org/uniprot/Q16832)
- OMIM: [https://omim.org/entry/191520](https://omim.org/entry/191520)