GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0038063 describes the signaling cascade triggered when collagen binds to receptor tyrosine kinases such as DDR1 and DDR2, leading to regulation of downstream cellular processes.
• DDR1 and DDR2 are the primary collagen-activated tyrosine kinase receptors, uniquely featuring discoidin domains that recognize native collagen.
• This pathway is implicated in cancer progression, fibrosis, and immune regulation, making it a therapeutic target.
• Collagen-activated RTK signaling influences cell migration, invasion, differentiation, and mechanosensing.
• Dysregulation of DDR signaling contributes to melanoma aggressiveness, colorectal cancer, myocardial fibrosis, and neuroblastoma cell fate.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are essential to dissect the causal roles of DDRs and downstream effectors.
Description
The collagen-activated tyrosine kinase receptor signaling pathway (GO:0038063) is a biological process initiated by the binding of collagen to receptor tyrosine kinases on the cell surface, culminating in the regulation of downstream cellular responses such as transcription, migration, and proliferation. This pathway is unique because it employs discoidin domain receptors (DDRs), which are the only known receptor tyrosine kinases activated by native collagens rather than soluble growth factors. The DDR family comprises DDR1 and DDR2, which exhibit distinct tissue distributions and ligand specificities, and their activation triggers a variety of signaling cascades that modulate cell behavior in development, homeostasis, and disease. Researchers study this pathway to understand how extracellular matrix cues are translated into intracellular signals, and to identify therapeutic targets for cancers, fibrotic disorders, and inflammatory conditions. The pathway's involvement in tumor progression, metastasis, and fibrosis underscores its clinical relevance and the need for robust experimental models to investigate its components and regulatory mechanisms.
collagen-activated tyrosine kinase receptor signaling pathway At A Glance
| GO ID | GO:0038063 |
|---|---|
| GO term | collagen-activated tyrosine kinase receptor signaling pathway |
| Ontology | biological_process |
| Synonym | collagen-activated RTK signaling pathway; collagen-activated tyrosine kinase receptor signalling pathway; DDR signaling pathway; discoidin domain receptor signaling pathway |
| Major function | Transduces collagen-derived extracellular signals into intracellular responses via tyrosine kinase receptors, regulating transcription, cell migration, proliferation, and differentiation. |
| Receptor type | Receptor tyrosine kinases (DDR1, DDR2) with discoidin homology domains. |
| Ligand | Native collagens (e.g., collagen I, II, III, IV). |
| Downstream processes | Regulation of transcription, cytoskeletal reorganization, cell adhesion, and mechanosensing. |
| Associated diseases | Cancer (melanoma, colorectal, neuroblastoma), fibrosis (myocardial, hepatic), and immune disorders. |
What Is GO:0038063?
According to the Gene Ontology, GO:0038063 is defined as the series of molecular signals initiated by collagen binding to its receptor on the surface of a target cell where the receptor possesses tyrosine kinase activity, and ending with the regulation of a downstream cellular process, e.g. transcription. This process is synonymous with collagen-activated RTK signaling pathway, DDR signaling pathway, and discoidin domain receptor signaling pathway. It encompasses the events from ligand-receptor interaction through intracellular phosphorylation events to changes in gene expression or other cellular outcomes.
Why Is collagen-activated tyrosine kinase receptor signaling pathway Important in Cell Biology?
The collagen-activated tyrosine kinase receptor signaling pathway is critical because it bridges the extracellular matrix to intracellular signaling, influencing fundamental processes such as cell growth, survival, and differentiation. Dysregulation of this pathway is increasingly recognized in cancer, where DDR1 and DDR2 promote tumor progression, invasion, and metastasis. In fibrotic diseases, DDR1 activation contributes to myocardial fibrosis and hepatic stellate cell activation. Understanding this pathway offers opportunities for targeted therapies and precision medicine, as evidenced by ongoing development of DDR modulators.
• Drives cancer progression by promoting cell migration and invasion in melanoma and colorectal cancer.
• Mediates fibrosis in heart and liver through DDR1 and DDR2 signaling.
• Regulates immune cell function and tumor immunology.
• Controls neuroblastoma cell fate decisions via mechanosensing.
• Involved in platelet activation through JAK2-dependent pathways.
• Serves as a target for small molecule inhibitors and biologics.
• Plays a role in tissue homeostasis and development.
• Enables crosstalk between extracellular matrix and intracellular signaling.
• Provides biomarkers for disease prognosis and therapeutic response.
• Facilitates mechanotransduction in various cell types.
What Happens During collagen-activated tyrosine kinase receptor signaling pathway?
Collagen Binding and Receptor Activation
In simple terms: Collagen, a structural protein outside cells, binds to specific receptors on the cell surface, switching them on.
The pathway begins when native collagens, such as collagen I or II, bind to the discoidin domain of DDR1 or DDR2. This binding induces receptor dimerization and autophosphorylation of tyrosine residues in the intracellular kinase domain, initiating downstream signaling. Unlike typical growth factor receptors, DDRs are activated slowly and persistently by collagen, leading to sustained signaling.
Intracellular Signaling Cascades
In simple terms: Activated receptors trigger a chain of molecular signals inside the cell, like a relay race.
Phosphorylated DDRs recruit adaptor proteins and kinases, activating pathways such as MAPK, PI3K/AKT, and JAK/STAT. For example, JAK2-dependent signaling has been implicated in platelet activation downstream of collagen receptors. These cascades amplify the signal and transmit it to various cellular compartments.
Regulation of Transcription and Cellular Responses
In simple terms: The signal reaches the nucleus, where it turns genes on or off, changing cell behavior.
Ultimately, the signaling leads to changes in gene expression, cytoskeletal reorganization, and cell fate decisions. In neuroblastoma, DDR2 signaling and mechanosensing orchestrate transcriptome changes that influence cell differentiation. In melanoma, DDR1 activation increases aggressiveness through kindlin-3 inactivation. These transcriptional and phenotypic outcomes define the pathway's biological impact.
Feedback and Crosstalk
In simple terms: The pathway can be tuned by other signals, like a dimmer switch.
DDR signaling intersects with other pathways, including insulin receptor signaling in hepatic stellate cells, where insulin resistance instigates liver fibrosis. Such crosstalk modulates the intensity and duration of the response, ensuring context-dependent outcomes.
Key Genes Involved in GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway
The key genes and proteins involved in collagen-activated tyrosine kinase receptor signaling include the receptors themselves, their ligands, and downstream effectors.
| Gene | Major Role | Research Relevance |
|---|---|---|
| DDR1 | Collagen receptor tyrosine kinase; activates downstream signaling | Implicated in cancer, fibrosis, and immune regulation |
| DDR2 | Collagen receptor tyrosine kinase; mediates mechanosensing | Roles in neuroblastoma, fibrosis, and development |
| COL1A1 | Major ligand (collagen I) for DDRs | Provides extracellular matrix cues; often overexpressed in fibrosis and cancer |
| COL2A1 | Ligand (collagen II) for DDR2 | Important in cartilage and bone development |
| JAK2 | Kinase downstream of collagen receptors | Mediates platelet activation |
| STAT | Transcription factors activated by JAK2 | Regulate gene expression in response to collagen |
| MAPK1 | Kinase in MAPK cascade | Transmits signals from DDRs to nucleus |
| PIK3CA | Catalytic subunit of PI3K | Activates AKT pathway downstream of DDRs |
| AKT1 | Serine/threonine kinase | Promotes cell survival and proliferation |
| SP1 | Transcription factor | Regulated by DDR1 in myocardial fibrosis |
| KIND3 | Kindlin-3, involved in integrin signaling | Inactivation increases melanoma aggressiveness via DDR1 |
| TGFB1 | Cytokine involved in fibrosis | Crosstalk with DDR signaling in hepatic stellate cells |
| INSR | Insulin receptor | Modulates TGFβ-induced activation in liver fibrosis |
| FN1 | Fibronectin, extracellular matrix protein | Cooperates with collagen in DDR activation |
| ITGB1 | Integrin beta 1 | Crosstalk with DDRs in mechanosensing |
| SRC | Non-receptor tyrosine kinase | Downstream of DDRs in cancer progression |
| PTK2 | Focal adhesion kinase | Mediates cytoskeletal changes downstream of DDRs |
How Is collagen-activated tyrosine kinase receptor signaling pathway Regulated?
The collagen-activated tyrosine kinase receptor signaling pathway is regulated at multiple levels. Receptor expression levels, collagen availability, and post-translational modifications modulate pathway activity. For instance, DDR1 ubiquitination and degradation are controlled by E3 ligases, and SP1 ubiquitination suppression by DDR1 contributes to myocardial fibrosis. Crosstalk with other signaling pathways, such as insulin receptor signaling, can influence DDR-mediated responses in hepatic stellate cells. Additionally, kindlin-3 inactivation alters DDR1 signaling in melanoma, highlighting intracellular regulators.
collagen-activated tyrosine kinase receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| DDR1 | Melanoma aggressiveness, colorectal cancer, myocardial fibrosis | Knockout or point-mutation in cancer cell lines; overexpression in fibroblasts |
| DDR2 | Neuroblastoma cell fate, fibrosis | Knockdown or knockout in neuroblastoma cells; knock-in of mutant DDR2 |
| JAK2 | Platelet activation, immune disorders | Point mutation (e.g., V617F) knock-in in hematopoietic cells |
| KIND3 | Melanoma progression | Knockout in melanoma cell lines |
| SP1 | Myocardial fibrosis | Overexpression or knockout in cardiac fibroblasts |
Cancer Progression and Metastasis
DDR1 and DDR2 are overexpressed in various cancers and promote migration, invasion, and metastasis. In melanoma, inactivation of kindlin-3 increases aggressiveness through DDR1. In colorectal cancer, DDR1 contributes to progression by promoting cell migration and invasion. DDR2 signaling in neuroblastoma influences cell fate and transcriptome changes. These findings position DDRs as therapeutic targets and biomarkers.
Fibrotic Diseases
DDR1 activation is implicated in myocardial fibrosis by suppressing SP1 ubiquitination and degradation in hypertensive rats. In liver fibrosis, insulin resistance instigates hepatic stellate cell activation via TGFβ, with crosstalk to DDR signaling. Targeting DDRs may offer anti-fibrotic strategies.
Immune and Inflammatory Conditions
DDRs modulate immune cell function and tumor immunology. JAK2-dependent pathways downstream of collagen receptors are involved in platelet activation, linking to thrombosis and inflammation. Understanding these roles can inform immunotherapies.
From collagen-activated tyrosine kinase receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does DDR1 kinase activity drive tumor invasion? | Kinase-dead point mutation knock-in in cancer cell lines |
| What is the role of DDR2 in mechanosensing? | Knockout or knockdown in neuroblastoma cells |
| How does collagen binding activate DDR1? | Tagged knock-in of DDR1 with fluorescent tag for imaging |
| Does kindlin-3 regulate DDR1 signaling? | Knockout of KIND3 in melanoma cells |
| Can DDR1 inhibition reverse fibrosis? | Overexpression of DDR1 in cardiac fibroblasts; treatment with inhibitors |
| What downstream genes are regulated by DDR signaling? | RNA-seq after DDR1 knockout or overexpression |
How to Study the collagen-activated tyrosine kinase receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss of gene function | Determine necessity of DDR1 in cancer |
| Point mutation knock-in | Effect of specific amino acid change | Assess kinase activity of DDR2 |
| RNA-seq | Global transcriptome changes | Identify downstream targets of DDR signaling |
| Phosphoproteomics | Phosphorylation events | Map immediate signaling nodes |
| Live-cell imaging | Receptor localization and dynamics | Visualize DDR1 activation |
| Traction force microscopy | Cell-generated forces | Study mechanosensing via DDR2 |
| Western blot | Protein expression and phosphorylation | Validate pathway activation |
| Immunohistochemistry | Tissue expression patterns | Correlate DDR levels with disease |
CRISPR-Cas9 Genome Editing
CRISPR-Cas9 is used to generate knockout, point mutation, and knock-in models to study DDR1, DDR2, and downstream effectors. For example, knockout of DDR1 in melanoma cells revealed its role in aggressiveness. Point mutations in the kinase domain can dissect catalytic activity.
Transcriptomic and Proteomic Profiling
RNA-seq and proteomics identify global changes in gene expression and protein phosphorylation upon pathway activation. In neuroblastoma, DDR2 signaling altered the transcriptome. Phosphoproteomics can map immediate downstream targets.
Imaging and Mechanosensing Assays
Live-cell imaging with tagged DDRs visualizes receptor trafficking and activation. Traction force microscopy measures mechanosensing downstream of DDR2. These methods link signaling to physical cues.
Pharmacological Inhibition
Small molecule inhibitors of DDRs are used to validate targets and assess therapeutic potential. Combining inhibitors with genetic models enhances rigor.
How CRISPR Can Be Used to Study GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway
Knockout
CRISPR knockout of DDR1 or DDR2 abolishes collagen-activated signaling, enabling loss-of-function studies. For instance, DDR1 knockout reduced melanoma aggressiveness. Knockout of KIND3 increased DDR1 signaling.
Point Mutation
Introducing kinase-dead or phospho-deficient point mutations in DDRs via CRISPR allows precise dissection of catalytic and docking functions. Such models help distinguish kinase-dependent from scaffold roles.
Knock-in
Knock-in of tagged DDRs (e.g., GFP) facilitates real-time imaging and interaction studies. Knock-in of disease-associated mutations can model human pathologies.
Overexpression
CRISPR activation or cDNA overexpression of DDRs or ligands amplifies pathway activity to study gain-of-function effects, such as fibrosis induction.
How EDITGENE Supports collagen-activated tyrosine kinase receptor signaling pathway Research
Researchers studying collagen-activated tyrosine kinase receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway regulation, disease progression, or therapeutic response. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation.
Contact EDITGENE today to design your custom CRISPR model for collagen-activated tyrosine kinase receptor signaling pathway research.
Frequently Asked Questions About collagen-activated tyrosine kinase receptor signaling pathway
What is GO:0038063?
GO:0038063 is the Gene Ontology term for collagen-activated tyrosine kinase receptor signaling pathway, describing how collagen binding to receptor tyrosine kinases like DDR1 and DDR2 triggers intracellular signals that regulate cellular processes.
What genes are involved in collagen-activated tyrosine kinase receptor signaling pathway?
Key genes include DDR1, DDR2, COL1A1, COL2A1, JAK2, STAT, MAPK1, PIK3CA, AKT1, and SP1, among others.
What are the synonyms for GO:0038063?
Synonyms include collagen-activated RTK signaling pathway, collagen-activated tyrosine kinase receptor signalling pathway, DDR signaling pathway, and discoidin domain receptor signaling pathway.
How is collagen-activated tyrosine kinase receptor signaling pathway regulated?
It is regulated by receptor expression, ligand availability, post-translational modifications, and crosstalk with other pathways such as insulin receptor signaling.
What diseases are associated with collagen-activated tyrosine kinase receptor signaling pathway?
It is implicated in cancers (melanoma, colorectal, neuroblastoma), fibrosis (myocardial, hepatic), and immune disorders.
What are DDR1 and DDR2?
DDR1 and DDR2 are discoidin domain receptor tyrosine kinases that bind native collagens and are the primary receptors in this pathway.
How can I study collagen-activated tyrosine kinase receptor signaling pathway?
Use CRISPR knockout, point mutation, knock-in, overexpression models, RNA-seq, phosphoproteomics, and imaging to dissect pathway components.
What is the role of DDR1 in cancer?
DDR1 promotes cancer progression by enhancing cell migration, invasion, and metastasis, as shown in melanoma and colorectal cancer.
What is the role of DDR2 in neuroblastoma?
DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through transcriptome changes.
How does collagen activate DDRs?
Collagen binds to the discoidin domain of DDRs, inducing dimerization and autophosphorylation of tyrosine residues, which initiates downstream signaling.
Conclusion
The collagen-activated tyrosine kinase receptor signaling pathway (GO:0038063) is a vital mechanism by which cells sense and respond to collagen in their environment. Through DDR1 and DDR2, this pathway regulates diverse processes and is implicated in cancer, fibrosis, and immune disorders. Continued research using advanced CRISPR models and multi-omics approaches will uncover new therapeutic opportunities. EDITGENE's suite of services supports these efforts by providing precise genetic tools.
References
- 1. Reger De Moura C et al.. 2024. Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1.. Oncogene 43(21):1620-1630 PMID: 38570692
- 2. Zhang H et al.. 2025. Discoidin Domain Receptors in Tumor Biology and Immunology: Progression and Challenge.. Biomolecules 15(6) PMID: 40563472
- 3. Lu WJ et al.. 2014. Role of a Janus kinase 2-dependent signaling pathway in platelet activation.. Thromb Res 133(6):1088-96 PMID: 24731555
- 4. Lee WH et al.. 2025. Insulin receptor responsiveness governs TGFβ-induced hepatic stellate cell activation: Insulin resistance instigates liver fibrosis.. FASEB J 39(5):e70427 PMID: 40022609
- 5. Vessella T et al.. 2024. DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through different transcriptome mechanisms.. FEBS Open Bio 14(5):867-882 PMID: 38538106
- 6. Lu D et al.. 2026. Discoidin Domain Receptor 1 Promotes Myocardial Fibrosis by Suppressing Specificity Protein 1 Ubiquitination and Degradation in Male Spontaneously Hypertensive Rats.. J Am Heart Assoc 15(6):e043251 PMID: 41778606
- 7. Zhang Y et al.. 2026. An updated review of discoidin domain receptor 1 (DDR1) modulators (2020-present).. Expert Opin Ther Pat 36(7):581-592 PMID: 42240164
- 8. Roumieux M et al.. 2026. Discoidin domain receptor 1 contributes to colorectal cancer progression by promoting cell migration and invasion.. Life Sci 402:124585 PMID: 42462480
