GO:0010641 positive regulation of platelet-derived growth factor receptor signaling pathway: Signaling Amplification, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0010641 describes any process that increases the frequency, rate or extent of the platelet-derived growth factor receptor (PDGFR) signaling pathway.
• PDGFR signaling is a receptor tyrosine kinase cascade that controls cell proliferation, migration, survival and differentiation in many tissues [1, 6].
• Positive regulation of PDGFR signaling is achieved by ligand availability, receptor expression levels, co-receptor interactions and downstream kinase amplification [5, 6].
• Dysregulated positive regulation of PDGFR signaling contributes to cancers such as melanoma and uterine cancer, and to inflammatory conditions such as obesity-associated hypothalamic inflammation [1, 5, 8].
• Key genes and proteins in this process include PDGF ligands (PDGFA, PDGFB, PDGFC, PDGFD), receptors (PDGFRA, PDGFRB), and downstream effectors such as PRKCD and NRAS [5, 6, 7].
• CRISPR knockout, point mutation, knock-in and overexpression models enable causal testing of candidate regulators of PDGFR signaling [5, 8].
Description
The Gene Ontology (GO) term GO:0010641, positive regulation of platelet-derived growth factor receptor signaling pathway, defines any biological process that increases the frequency, rate or extent of the platelet-derived growth factor receptor (PDGFR) signaling pathway. PDGFR signaling is initiated when PDGF ligands bind to PDGFRA or PDGFRB receptor tyrosine kinases, leading to receptor autophosphorylation and activation of downstream cascades that control cell proliferation, migration, survival and differentiation [1, 6]. Because this pathway is central to tissue remodeling, angiogenesis and inflammation, understanding how it is positively regulated is critical for both developmental biology and disease research [1, 7].
positive regulation of platelet-derived growth factor receptor signaling pathway At A Glance
| GO ID | GO:0010641 |
|---|---|
| GO term | positive regulation of platelet-derived growth factor receptor signaling pathway |
| Ontology | biological_process |
| Synonym | positive regulation of platelet-derived growth factor receptor signalling pathway |
| Definition | Any process that increases the frequency, rate or extent of the platelet-derived growth factor receptor signaling pathway. |
| Major function | Amplification of PDGFR-mediated cellular responses such as proliferation, migration and survival. |
| Related ligands | PDGFA, PDGFB, PDGFC, PDGFD |
| Related receptors | PDGFRA, PDGFRB |
| Example downstream effectors | PRKCD, NRAS, PI3K/AKT, MAPK |
What Is GO:0010641?
GO:0010641 is a biological process term that encompasses any mechanism that amplifies or sustains signaling through platelet-derived growth factor receptors. This includes increased ligand availability, elevated receptor expression, enhanced receptor dimerization or kinase activity, and downstream events that prolong or intensify the signal [1, 6]. The term is the positive counterpart of negative regulation of PDGFR signaling and is distinct from the receptor signaling pathway itself (GO:0035791 or related terms).
Why Is positive regulation of platelet-derived growth factor receptor signaling pathway Important in Cell Biology?
Positive regulation of PDGFR signaling is important because it governs fundamental processes such as embryonic development, wound healing, angiogenesis and tissue homeostasis, and its dysregulation is implicated in cancer, fibrosis and inflammation [1, 5, 7]. For researchers, this GO term provides a framework to identify and characterize genes and mechanisms that enhance PDGFR signaling, which can reveal therapeutic targets and biomarkers.
• PDGFR signaling amplification promotes tumor cell proliferation and survival in cancers such as melanoma and uterine cancer [5, 8].
• Positive regulation of PDGFR signaling in pericytes contributes to hypothalamic inflammation and obesity.
• PDGFR alpha expression dynamics are critical for alveolar fibroblast-mediated lung repair.
• PDGFR signaling in subchondral bone osteoclasts is linked to osteoarthritis progression.
• Axonal guidance signaling, which intersects with PDGFR pathways, is suppressed in nasal polyps.
• PDGFR alpha positive cells modulate purinergic inhibitory nerve-smooth muscle transmission.
• The pathway is a target for kinase inhibitors in oncology and for modulating tissue remodeling [5, 8].
• Understanding positive regulation helps design CRISPR screens to identify novel enhancers of PDGFR signaling [5, 6].
What Happens During positive regulation of platelet-derived growth factor receptor signaling pathway?
Ligand availability and receptor binding
In simple terms: More growth factor ligand around means more signal can be triggered.
Positive regulation often begins with increased expression or release of PDGF ligands (PDGFA, PDGFB, PDGFC, PDGFD), which bind and activate PDGFRA or PDGFRB [1, 7]. In pericytes, PDGF signaling promotes hypothalamic inflammation and obesity, indicating that ligand-driven activation is a key positive regulatory step.
Receptor expression and dimerization
In simple terms: More receptors on the cell surface can catch more ligand and send a stronger signal.
Upregulation of PDGFRA or PDGFRB increases the number of available receptors for ligand binding and subsequent dimerization and autophosphorylation [5, 7]. Dynamic regulation of PDGFRA expression in alveolar fibroblasts during realveolarization demonstrates how receptor levels control pathway output.
Downstream kinase amplification
In simple terms: Once the receptor is active, it switches on other proteins that keep the signal going.
Activated PDGFRs phosphorylate downstream effectors, including protein kinase C-delta (PRKCD), which is stimulated by PDGF beta receptor signaling. This kinase cascade amplifies and propagates the signal to transcription factors and other cellular machinery.
Crosstalk with other signaling pathways
In simple terms: Other pathways can boost or sustain the PDGF signal.
Positive regulation can occur through crosstalk with pathways such as PGE2-EP4 signaling in osteoclasts, which regulates osteoarthritis and may intersect with PDGFR signaling. Additionally, axonal guidance signaling pathways are suppressed in nasal polyps, suggesting context-dependent modulation of PDGFR-related networks.
Feedback and sustained activation
In simple terms: Cells can keep the signal active by reducing negative feedback or increasing positive feedback.
Melanomas acquire resistance to B-RAF(V600E) inhibition by upregulating receptor tyrosine kinases including PDGFRs or N-RAS, illustrating how positive regulation can sustain signaling under therapeutic pressure. This highlights the importance of feedback loops in controlling PDGFR pathway intensity.
Key Genes Involved in GO:0010641 positive regulation of platelet-derived growth factor receptor signaling pathway
The following genes and proteins are central to the positive regulation of PDGFR signaling, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PDGFA | PDGF ligand that activates PDGFRA | Studied in development and cancer [1, 7] |
| PDGFB | PDGF ligand that activates PDGFRB | Implicated in fibrosis and inflammation |
| PDGFC | PDGF ligand for PDGFRA/B | Role in tissue remodeling |
| PDGFD | PDGF ligand for PDGFRB | Potential target in cancer |
| PDGFRA | Receptor tyrosine kinase | Key mediator of signaling; target in uterine cancer |
| PDGFRB | Receptor tyrosine kinase | Activates PRKCD and downstream pathways |
| PRKCD | Protein kinase C-delta | Downstream effector of PDGFRB signaling |
| NRAS | Small GTPase | Upregulated in melanoma resistance to B-RAF inhibition |
| EP4 | Prostaglandin E2 receptor | Regulates osteoclasts in osteoarthritis |
| PGE2 | Prostaglandin ligand | Activates EP4 and may crosstalk with PDGFR |
| AXON GUIDANCE GENES | Pathway components | Suppressed in nasal polyps |
| P2RY receptors | Purinergic receptors | Modulate nerve-smooth muscle transmission with PDGFRA cells |
| B-RAF | Serine/threonine kinase | Melanoma driver; resistance via PDGFR upregulation |
| PI3K/AKT | Downstream signaling | Promotes survival and proliferation |
| MAPK/ERK | Downstream signaling | Controls proliferation and differentiation |
| STAT3 | Transcription factor | Potential downstream effector |
| FGF | Fibroblast growth factor | Crosstalk with PDGFR in repair |
How Is positive regulation of platelet-derived growth factor receptor signaling pathway Regulated?
Positive regulation of PDGFR signaling is controlled at multiple levels. Ligand expression can be induced by inflammatory cytokines and growth factors. Receptor levels are dynamically regulated, as seen for PDGFRA in alveolar fibroblasts during realveolarization. Downstream kinases such as PRKCD and NRAS can amplify the signal [5, 6]. Additionally, crosstalk with prostaglandin and purinergic pathways modulates pathway activity in specific tissues [2, 4].
positive regulation of platelet-derived growth factor receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PDGFRA | Uterine cancer | PDGFRA knockout or knockdown in uterine cancer cell lines |
| PDGFRB | Melanoma resistance | PDGFRB overexpression in melanoma cells with B-RAF(V600E) mutation |
| NRAS | Melanoma | NRAS point mutation knock-in in melanoma cell lines |
| PDGFB | Obesity-associated hypothalamic inflammation | Pericyte-specific PDGFB knockout in mouse models |
| EP4 | Osteoarthritis | EP4 knockout in osteoclasts or subchondral bone |
Cancer
Positive regulation of PDGFR signaling promotes tumor growth and resistance to targeted therapies. In melanoma, upregulation of receptor tyrosine kinases including PDGFRs or N-RAS confers resistance to B-RAF(V600E) inhibition. In uterine cancer, PDGFRA blockade reduces cell proliferation and survival, highlighting the receptor as a therapeutic target.
Metabolic and inflammatory disorders
PDGF signaling in pericytes promotes hypothalamic inflammation and obesity, linking positive regulation of this pathway to metabolic disease. This suggests that inhibitors of PDGFR signaling could be explored for obesity-related inflammation.
Osteoarthritis
PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis, and this pathway may intersect with PDGFR signaling in bone remodeling. Positive regulation of PDGFR signaling in osteoclasts could contribute to joint destruction.
Respiratory and nasal diseases
Axonal guidance signaling pathways are suppressed in human nasal polyps, and PDGFR alpha expression is dynamically regulated in alveolar fibroblasts during lung repair [3, 7]. These findings link positive regulation of PDGFR signaling to airway remodeling and repair processes [3, 7].
From positive regulation of platelet-derived growth factor receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene reduce PDGFR signaling? | CRISPR knockout in cell lines (e.g., PDGFRA KO) |
| Does a specific mutation enhance PDGFR activity? | Point mutation knock-in (e.g., NRAS mutation) |
| Does overexpression of a ligand increase signaling? | Overexpression of PDGFA or PDGFB in target cells |
| Can we tag endogenous PDGFR for live imaging? | Knock-in of fluorescent tag at PDGFRA locus |
| Which genes regulate PDGFR signaling in a genome-wide manner? | CRISPR library screening |
| Does tissue-specific PDGFR signaling drive disease? | Conditional knockout in pericytes or osteoclasts [1, 2] |
How to Study the positive regulation of platelet-derived growth factor receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function effects | Test if PDGFRA is required for signaling |
| Point mutation knock-in | Gain-of-function or resistance mutations | Model NRAS mutation in melanoma |
| Overexpression | Sufficiency of a gene to activate pathway | Overexpress PDGFB in pericytes |
| RNA-seq | Transcriptional changes | Identify downstream targets of PDGFR |
| Phospho-immunoblotting | Receptor and kinase activation | Measure PDGFR autophosphorylation |
| Proliferation assay | Cell growth | Assess effect of PDGFR blockade |
| Migration assay | Cell motility | Study PDGFR-driven migration |
| CRISPR library screen | Genome-wide regulators | Discover positive regulators of PDGFR signaling |
CRISPR knockout and point mutation
CRISPR-Cas9 knockout of PDGFRA or PDGFRB can determine their requirement for signaling, while point mutations (e.g., in NRAS) can mimic activating events seen in melanoma [5, 8].
Knock-in and overexpression
Knock-in of tags or reporters allows visualization of receptor dynamics, and overexpression of ligands or receptors can test sufficiency for pathway activation [1, 7].
Transcriptomics and proteomics
RNA-seq and proteomics can identify genes and proteins whose expression changes upon PDGFR pathway modulation, revealing positive regulators [1, 6].
Functional assays
Proliferation, migration and survival assays, as well as phospho-specific immunoblotting for PDGFR and downstream kinases, measure pathway output [5, 6].
How CRISPR Can Be Used to Study GO:0010641 positive regulation of platelet-derived growth factor receptor signaling pathway
Knockout
CRISPR knockout of PDGFRA or PDGFRB ablates receptor expression and signaling, providing a clean background to test positive regulators. Knockout of downstream effectors like PRKCD can reveal their contribution to pathway amplification.
Point Mutation
Point mutation knock-in can model activating mutations in NRAS or other components that enhance PDGFR signaling, as seen in melanoma resistance. This approach helps dissect specific amino acid contributions to pathway activity.
Knock-in
Knock-in of fluorescent or affinity tags at endogenous PDGFRA or PDGFRB loci enables real-time tracking of receptor expression and localization, as demonstrated for PDGFRA in alveolar fibroblasts.
Overexpression
Overexpression of PDGF ligands or receptors can test whether increased dosage is sufficient to drive positive regulation, as shown for PDGFB in pericytes and PDGFRB in melanoma [1, 5].
How EDITGENE Supports positive regulation of platelet-derived growth factor receptor signaling pathway Research
Researchers studying positive regulation of platelet-derived growth factor receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway amplification. EDITGENE provides CRISPR-based services to generate precisely engineered cell models for such functional studies.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of platelet-derived growth factor receptor signaling pathway research.
Frequently Asked Questions About positive regulation of platelet-derived growth factor receptor signaling pathway
What is GO:0010641?
GO:0010641 is the Gene Ontology term for positive regulation of platelet-derived growth factor receptor signaling pathway, describing any process that increases the frequency, rate or extent of PDGFR signaling.
What genes are involved in positive regulation of PDGFR signaling?
Key genes include PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, PDGFRB, PRKCD and NRAS, among others [1, 5, 6, 7].
How is PDGFR signaling positively regulated?
It is positively regulated by increased ligand availability, receptor upregulation, downstream kinase amplification and crosstalk with other pathways [1, 5, 6].
What diseases are linked to PDGFR signaling?
Cancers such as melanoma and uterine cancer, obesity-associated hypothalamic inflammation, osteoarthritis and nasal polyps have been linked to PDGFR signaling [1, 2, 3, 5, 8].
What is the role of PDGFRA in disease?
PDGFRA is a receptor tyrosine kinase whose expression and activity are associated with uterine cancer and lung repair processes [7, 8].
How can CRISPR be used to study PDGFR signaling?
CRISPR knockout, point mutation, knock-in and overexpression can test the causal role of specific genes in PDGFR signaling [5, 6, 7, 8].
What is the relationship between PDGFR and melanoma resistance?
Melanomas can acquire resistance to B-RAF(V600E) inhibition by upregulating receptor tyrosine kinases including PDGFRs or N-RAS.
Does PDGFR signaling affect obesity?
Yes, PDGF signaling in pericytes promotes hypothalamic inflammation and obesity in mouse models.
What experimental models are used to study positive regulation of PDGFR signaling?
Common models include CRISPR knockout cell lines, point mutation knock-ins, overexpression lines and conditional knockout mice [1, 5, 8].
How does EDITGENE support PDGFR signaling research?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening and bioinformatics services for PDGFR-related genes [5, 6, 7, 8].
Conclusion
GO:0010641 provides a precise framework for studying how PDGFR signaling is amplified in health and disease. Understanding its mechanisms and key genes can reveal therapeutic targets for cancer, metabolic disorders and tissue repair. EDITGENE offers comprehensive CRISPR services to accelerate this research.
References
- 1. Okekawa A et al.. 2024. Platelet-derived growth factor signaling in pericytes promotes hypothalamic inflammation and obesity.. Mol Med 30(1):21 PMID: 38317079
- 2. Jiang W et al.. 2022. PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis.. Bone Res 10(1):27 PMID: 35260562
- 3. Wu D et al.. 2018. Axonal Guidance Signaling Pathway Is Suppressed in Human Nasal Polyps.. Am J Rhinol Allergy 32(4):208-216 PMID: 29754498
- 4. Huang X et al.. 2020. [Role of platelet-derived growth factor receptor α positive cells in purinergic inhibitory nerve-smooth muscle transmission].. Sheng Li Xue Bao 72(3):391-398 PMID: 32572436
- 5. Nazarian R et al.. 2010. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation.. Nature 468(7326):973-7 PMID: 21107323
- 6. Li W et al.. 1994. Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta.. Mol Cell Biol 14(10):6727-35 PMID: 7935392
- 7. Chen L et al.. 2012. Dynamic regulation of platelet-derived growth factor receptor α expression in alveolar fibroblasts during realveolarization.. Am J Respir Cell Mol Biol 47(4):517-27 PMID: 22652199
- 8. Roh JW et al.. 2014. Biologic effects of platelet-derived growth factor receptor α blockade in uterine cancer.. Clin Cancer Res 20(10):2740-50 PMID: 24634380
