GO:2000587 negative regulation of platelet-derived growth factor receptor-beta signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2000587 describes any process that stops, prevents, or reduces the frequency, rate, or extent of platelet-derived growth factor receptor-beta (PDGFR-beta) signaling.
• PDGFR-beta signaling is a major driver of smooth muscle cell proliferation, migration, and neointimal hyperplasia, and its negative regulation is critical for vascular homeostasis.
• Key negative regulators include PTPN14, Cbl, Sestrin 2, and phospholipase C gamma 1, which act at receptor, adaptor, or transcriptional levels.
• Dysregulated negative regulation of PDGFR-beta signaling contributes to neointimal hyperplasia, intracranial aneurysm, gastric carcinoma, and glomerular mesangial cell proliferation.
• CRISPR knockout, point mutation, knock-in, and overexpression models enable causal dissection of negative regulators in relevant cell types.
• Understanding this process informs therapeutic strategies targeting PDGFR-beta signaling in vascular and neoplastic diseases.
Description
The platelet-derived growth factor receptor-beta (PDGFR-beta) signaling pathway is a central regulator of cell proliferation, migration, and survival in mesenchymal cells, including vascular smooth muscle cells and fibroblasts. Its activity is tightly controlled by multiple negative regulatory mechanisms that prevent excessive or prolonged signaling. GO:2000587, negative regulation of platelet-derived growth factor receptor-beta signaling pathway, captures any process that stops, prevents, or reduces the frequency, rate, or extent of this signaling cascade. This term is essential for researchers studying vascular biology, cancer, and fibrotic diseases because loss of negative regulation can drive pathological cell proliferation and tissue remodeling. Negative regulation of PDGFR-beta signaling occurs through diverse molecular mechanisms, including receptor dephosphorylation by protein tyrosine phosphatases, ubiquitination and degradation of the receptor, and modulation of downstream effectors such as Erk1/2 and Akt. For example, PTPN14 has been shown to aggravate neointimal hyperplasia by boosting PDGFR-beta signaling in smooth muscle cells, indicating that its normal function may be context-dependent. Cbl binding to a phospholipase C gamma 1-docking site on PDGFR-beta provides a dual mechanism of negative regulation, affecting both receptor stability and downstream signaling. Sestrin 2 regulates PDGFR-beta expression by modulating proteasomal and Nrf2 transcription factor functions. These findings highlight the complexity and importance of negative regulation in maintaining cellular homeostasis. This article provides a comprehensive overview of GO:2000587, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and experimental models. It is designed for researchers seeking to understand how negative regulation of PDGFR-beta signaling is studied and manipulated using CRISPR-based approaches and other molecular techniques.
negative regulation of platelet-derived growth factor receptor-beta signaling pathway At A Glance
| GO ID | GO:2000587 |
|---|---|
| GO term | negative regulation of platelet-derived growth factor receptor-beta signaling pathway |
| Ontology | biological_process |
| Synonym | negative regulation of betaPDGF receptor signaling pathway; negative regulation of PDGFR-beta signaling pathway; negative regulation of PDGF receptor-beta signaling pathway; negative regulation of platelet-derived growth factor receptor-beta signalling pathway |
| Major function | Attenuation or termination of PDGFR-beta-mediated intracellular signaling to prevent excessive cell proliferation, migration, and survival |
| Key regulators | PTPN14, Cbl, Sestrin 2, phospholipase C gamma 1, and other modulators of receptor trafficking and downstream effectors |
| Associated diseases | Neointimal hyperplasia, intracranial aneurysm, gastric carcinoma, glomerular mesangial cell proliferation |
| Research methods | CRISPR knockout/knock-in, RNA-seq, proteomics, phospho-proteomics, imaging |
What Is GO:2000587?
GO:2000587, negative regulation of platelet-derived growth factor receptor-beta signaling pathway, is a biological process defined as any process that stops, prevents, or reduces the frequency, rate, or extent of platelet-derived growth factor receptor-beta signaling pathway. This includes mechanisms that act directly on the receptor, such as dephosphorylation or degradation, as well as those that modulate downstream signaling components or feedback loops.
Why Is negative regulation of platelet-derived growth factor receptor-beta signaling pathway Important in Cell Biology?
Negative regulation of PDGFR-beta signaling is crucial for preventing uncontrolled cell proliferation and migration, which are hallmarks of vascular proliferative diseases and cancer. Dysregulation of this process can lead to neointimal hyperplasia after vascular injury, intracranial aneurysm formation, and tumor progression. Understanding the molecular players and mechanisms that negatively regulate PDGFR-beta signaling provides opportunities for therapeutic intervention and for developing targeted CRISPR models to study disease mechanisms.
• Prevents excessive smooth muscle cell proliferation and neointimal hyperplasia after vascular injury.
• Maintains vascular wall integrity and prevents intracranial aneurysm formation under shear stress.
• Limits tumor growth and progression in cancers such as gastric carcinoma.
• Regulates glomerular mesangial cell proliferation and extracellular matrix accumulation in kidney disease.
• Controls the duration and amplitude of downstream Erk1/2 and Akt signaling.
• Provides feedback mechanisms to avoid chronic inflammation and fibrosis.
• Serves as a target for therapeutic modulation in cardiovascular and oncological diseases.
• Enables precise dissection of signaling networks using CRISPR-based gene editing.
What Happens During negative regulation of platelet-derived growth factor receptor-beta signaling pathway?
Receptor Dephosphorylation and Inactivation
In simple terms: Enzymes remove phosphate groups from the receptor to switch off its signal.
Protein tyrosine phosphatases, such as PTPN14, can dephosphorylate PDGFR-beta and attenuate its kinase activity. However, PTPN14 has also been shown to aggravate neointimal hyperplasia by boosting PDGFR-beta signaling in smooth muscle cells, suggesting context-dependent roles. Cbl binding to a phospholipase C gamma 1-docking site on PDGFR-beta provides a dual mechanism of negative regulation, involving receptor ubiquitination and degradation.
Ubiquitination and Degradation of PDGFR-beta
In simple terms: Tagging the receptor for destruction reduces its availability.
The E3 ubiquitin ligase Cbl is recruited to activated PDGFR-beta and promotes its ubiquitination, leading to lysosomal or proteasomal degradation. This process limits the duration of signaling and is a key negative regulatory mechanism. Sestrin 2 regulates PDGFR-beta expression by modulating proteasomal and Nrf2 transcription factor functions, further linking degradation pathways to receptor levels.
Modulation of Downstream Effectors
In simple terms: Turning off the signals that the receptor sends inside the cell.
Negative regulation can occur at the level of downstream effectors such as Erk1/2 and Akt. For instance, Akt serine threonine kinase regulates PDGF-induced DNA synthesis in glomerular mesangial cells by modulating c-fos and p27(kip1) expression. The temporal pattern of Erk1/2 phosphorylation is also interconnected with other signaling pathways, providing additional layers of negative control.
Transcriptional and Feedback Regulation
In simple terms: The cell adjusts how much receptor is made in response to signals.
Sestrin 2 modulates PDGFR-beta expression by influencing Nrf2 transcription factor function and proteasomal activity. This transcriptional and post-translational feedback ensures that receptor levels are adapted to cellular needs. Additionally, Myc is essential for transformation by TEL/PDGFR-beta, indicating that oncogenic signaling can override normal negative regulation.
Key Genes Involved in GO:2000587 negative regulation of platelet-derived growth factor receptor-beta signaling pathway
The following genes and proteins are key players in the negative regulation of PDGFR-beta signaling, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PTPN14 | Protein tyrosine phosphatase that can dephosphorylate PDGFR-beta; context-dependent effects on neointimal hyperplasia | Vascular smooth muscle cell proliferation; target for neointimal hyperplasia |
| Cbl | E3 ubiquitin ligase that promotes PDGFR-beta ubiquitination and degradation; binds to PLC-gamma1 docking site | Negative regulation of receptor stability; cancer and vascular biology |
| Sestrin 2 (SESN2) | Regulates PDGFR-beta expression via proteasomal and Nrf2 transcription factor functions | Oxidative stress response; receptor level control |
| PLCG1 | Phospholipase C gamma 1; its docking site on PDGFR-beta mediates Cbl binding and negative regulation | Downstream signaling modulation |
| PDGFRB | Platelet-derived growth factor receptor beta; the central receptor tyrosine kinase | Target of negative regulation; driver of proliferation |
| PDGFB | Platelet-derived growth factor B; ligand for PDGFR-beta | Paracrine signaling in aneurysm and cancer |
| AKT1 | Serine/threonine kinase downstream of PDGFR-beta; regulates DNA synthesis and gene expression | Glomerular mesangial cell proliferation |
| MYC | Transcription factor essential for transformation by TEL/PDGFR-beta | Oncogenic signaling; leukemia |
| NRF2 (NFE2L2) | Transcription factor modulated by Sestrin 2 to regulate PDGFR-beta expression | Oxidative stress and receptor regulation |
| ERK1/2 (MAPK3/MAPK1) | Downstream kinases whose phosphorylation pattern is regulated by interconnected signaling | Temporal signaling dynamics |
| PIEZO1 | Mechanosensitive ion channel; its downregulation under shear stress promotes PDGF-BB/PDGFR-beta paracrine signaling | Intracranial aneurysm formation |
| CDH1 (E-cadherin) | Cell adhesion molecule; its expression correlates with PDGFB and PDGFR-beta in gastric carcinoma | Tumor progression and metastasis |
| P27KIP1 (CDKN1B) | Cyclin-dependent kinase inhibitor regulated by Akt in mesangial cells | Cell cycle control |
| C-FOS (FOS) | Immediate early gene regulated by Akt in PDGF-induced DNA synthesis | Proliferation and gene expression |
| TEL/PDGFRB fusion | Oncogenic fusion protein that requires Myc for transformation | Myeloproliferative disorders |
| PTPN11 (SHP2) | Potential phosphatase involved in PDGFR-beta signaling modulation (implied by general mechanisms) | Signaling crosstalk |
| SOCS proteins | Suppressors of cytokine signaling that may modulate PDGFR-beta signaling (generic) | Feedback inhibition |
| GRB2 | Adaptor protein that links PDGFR-beta to downstream pathways (generic) | Signal transduction |
How Is negative regulation of platelet-derived growth factor receptor-beta signaling pathway Regulated?
Negative regulation of PDGFR-beta signaling is itself subject to regulation by various cellular inputs. For example, Sestrin 2 modulates PDGFR-beta expression through proteasomal and Nrf2 transcription factor functions, linking oxidative stress to receptor levels. The temporal pattern of Erk1/2 phosphorylation is regulated by interconnected signaling pathways, providing dynamic feedback. Additionally, high shear stress-induced endothelial Piezo1 downregulation promotes PDGF-BB/PDGFR-beta paracrine signaling, indicating that mechanical forces can influence negative regulation. These layers of regulation ensure that PDGFR-beta signaling is appropriately attenuated in response to environmental cues.
negative regulation of platelet-derived growth factor receptor-beta signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PTPN14 | Neointimal hyperplasia | Smooth muscle cell-specific knockout or overexpression in mouse vascular injury model |
| PDGFB/PDGFRB | Intracranial aneurysm | Endothelial cell-specific Piezo1 knockout or PDGFRB knock-in in mouse |
| PDGFB/PDGFRB | Gastric carcinoma | Gastric cancer cell lines with PDGFRB knockout or overexpression |
| AKT1 | Glomerular mesangial cell proliferation | Mesangial cell lines with Akt1 knockout or point mutation |
| MYC | TEL/PDGFR-beta-induced leukemia | Bone marrow transplantation model with Myc knockout or knockdown |
Neointimal Hyperplasia and Vascular Disease
Neointimal hyperplasia is a major cause of restenosis after vascular interventions. PTPN14 has been shown to aggravate neointimal hyperplasia by boosting PDGFR-beta signaling in smooth muscle cells, highlighting the importance of negative regulation in this context. Loss of negative regulators can lead to excessive smooth muscle cell proliferation and migration, contributing to vascular occlusion.
Intracranial Aneurysm
High shear stress-induced endothelial Piezo1 downregulation promotes intracranial aneurysm formation via the PDGF-BB/PDGFR-beta paracrine signaling pathway. This suggests that impaired negative regulation of PDGFR-beta signaling under hemodynamic stress contributes to aneurysm pathogenesis.
Gastric Carcinoma
Clinicopathological significance of PDGFB, PDGFR-beta, and E-cadherin expression has been observed in gastric carcinoma, where dysregulated PDGFR-beta signaling may promote tumor progression. Negative regulation of this pathway is therefore relevant to cancer biology.
Glomerular Mesangial Cell Proliferation
Akt serine threonine kinase regulates PDGF-induced DNA synthesis in glomerular mesangial cells by modulating c-fos and p27(kip1) gene expression. Dysregulation of negative regulation can lead to mesangial cell proliferation, a hallmark of glomerulonephritis and diabetic nephropathy.
From negative regulation of platelet-derived growth factor receptor-beta signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of PTPN14 enhance PDGFR-beta signaling and neointimal hyperplasia? | PTPN14 knockout mouse or smooth muscle cell-specific knockout |
| Does Cbl-mediated ubiquitination require the PLC-gamma1 docking site on PDGFR-beta? | PDGFR-beta point mutant (Y1009F or similar) knock-in cells |
| How does Sestrin 2 regulate PDGFR-beta expression? | SESN2 knockout and overexpression cell lines |
| What is the role of Piezo1 in shear stress-induced PDGFR-beta signaling? | Endothelial-specific Piezo1 knockout mouse |
| Does Akt1 regulate mesangial cell proliferation via c-fos and p27? | Akt1 knockout mesangial cells |
| Can overexpression of a negative regulator suppress tumor growth? | Xenograft models with inducible overexpression of candidate negative regulators |
How to Study the negative regulation of platelet-derived growth factor receptor-beta signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Loss-of-function effects on PDGFR-beta signaling | Identify novel negative regulators |
| Phospho-proteomics | Phosphorylation status of PDGFR-beta and downstream targets | Quantify signaling dynamics |
| RNA-seq | Transcriptional changes upon perturbation | Identify feedback mechanisms |
| Proteasome inhibition | Protein stability of PDGFR-beta | Assess degradation pathways |
| Live-cell imaging | Receptor internalization and trafficking | Visualize negative regulation |
| EdU proliferation assay | DNA synthesis and cell proliferation | Measure functional outcomes |
| Co-immunoprecipitation | Protein-protein interactions (e.g., Cbl-PDGFR-beta) | Map regulatory complexes |
CRISPR-Based Genetic Screens
Genome-wide CRISPR knockout or activation screens can identify novel negative regulators of PDGFR-beta signaling. Cells are stimulated with PDGF-BB and assessed for downstream phosphorylation of Erk1/2 or Akt, followed by sequencing to identify enriched sgRNAs.
Phospho-Proteomics and Signaling Profiling
Mass spectrometry-based phospho-proteomics can quantify changes in PDGFR-beta phosphorylation and downstream signaling upon genetic perturbation. This approach reveals the dynamics of negative regulation and crosstalk with other pathways.
Transcriptional and Proteasomal Regulation Assays
RNA-seq and proteasome inhibition experiments can dissect how negative regulators such as Sestrin 2 modulate PDGFR-beta expression at the transcriptional and post-translational levels.
Imaging and Proliferation Assays
Live-cell imaging of fluorescently tagged PDGFR-beta and proliferation assays (e.g., EdU incorporation) can visualize receptor trafficking and cell cycle progression in response to negative regulators.
How CRISPR Can Be Used to Study GO:2000587 negative regulation of platelet-derived growth factor receptor-beta signaling pathway
Knockout
CRISPR knockout of candidate negative regulators (e.g., PTPN14, Cbl, SESN2) in vascular smooth muscle cells or cancer cell lines can reveal their causal role in attenuating PDGFR-beta signaling. For example, PTPN14 knockout may reduce neointimal hyperplasia in mouse models.
Point Mutation
Introducing point mutations in PDGFR-beta (e.g., at the PLC-gamma1 docking site) can disrupt Cbl binding and prevent negative regulation, leading to enhanced signaling. This approach helps map specific phosphotyrosine residues required for negative regulation.
Knock-in
Knock-in of tagged PDGFR-beta (e.g., GFP or HA) allows real-time tracking of receptor localization and degradation. Knock-in of disease-associated mutations can model aberrant negative regulation.
Overexpression
Overexpression of negative regulators such as Sestrin 2 or Cbl can suppress PDGFR-beta signaling and reduce pathological cell proliferation. This is useful for validating therapeutic targets.
How EDITGENE Supports negative regulation of platelet-derived growth factor receptor-beta signaling pathway Research
Researchers studying negative regulation of platelet-derived growth factor receptor-beta signaling pathway-related genes often need to determine whether a candidate gene is causally involved in attenuating or terminating PDGFR-beta signaling. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of platelet-derived growth factor receptor-beta signaling pathway research.
Frequently Asked Questions About negative regulation of platelet-derived growth factor receptor-beta signaling pathway
What is GO:2000587?
GO:2000587 is the Gene Ontology term for negative regulation of platelet-derived growth factor receptor-beta signaling pathway, defined as any process that stops, prevents, or reduces the frequency, rate, or extent of PDGFR-beta signaling.
What genes are involved in negative regulation of PDGFR-beta signaling?
Key genes include PTPN14, Cbl, Sestrin 2, and phospholipase C gamma 1, among others.
How does Cbl negatively regulate PDGFR-beta?
Cbl binds to a phospholipase C gamma 1-docking site on PDGFR-beta and promotes its ubiquitination and degradation, providing a dual mechanism of negative regulation.
What diseases are associated with impaired negative regulation of PDGFR-beta signaling?
Neointimal hyperplasia, intracranial aneurysm, gastric carcinoma, and glomerular mesangial cell proliferation are associated with dysregulated PDGFR-beta signaling.
How can CRISPR be used to study negative regulation of PDGFR-beta signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise manipulation of candidate genes to assess their impact on PDGFR-beta signaling.
What is the role of Sestrin 2 in PDGFR-beta regulation?
Sestrin 2 regulates PDGFR-beta expression by modulating proteasomal and Nrf2 transcription factor functions.
What is the significance of PTPN14 in neointimal hyperplasia?
PTPN14 aggravates neointimal hyperplasia by boosting PDGFR-beta signaling in smooth muscle cells, indicating a context-dependent role.
How does shear stress affect PDGFR-beta signaling in intracranial aneurysm?
High shear stress-induced endothelial Piezo1 downregulation promotes intracranial aneurysm formation via the PDGF-BB/PDGFR-beta paracrine signaling pathway.
What methods are used to study negative regulation of PDGFR-beta signaling?
Common methods include CRISPR screens, phospho-proteomics, RNA-seq, proteasome inhibition, and imaging-based assays.
Why is negative regulation of PDGFR-beta signaling important for cancer?
It prevents excessive cell proliferation and survival; loss of negative regulation can contribute to tumor progression, as seen in gastric carcinoma.
Conclusion
GO:2000587, negative regulation of platelet-derived growth factor receptor-beta signaling pathway, is a critical biological process that maintains cellular homeostasis by attenuating PDGFR-beta signaling. Dysregulation of this process is implicated in vascular diseases, cancer, and kidney disorders. Understanding the molecular players and mechanisms through CRISPR-based models offers promising avenues for therapeutic intervention. EDITGENE provides comprehensive services to support research in this field.
References
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- 2. Jurek A et al.. 2011. Platelet-derived growth factor-induced signaling pathways interconnect to regulate the temporal pattern of Erk1/2 phosphorylation.. Cell Signal 23(1):280-7 PMID: 20851764
- 3. Reddi AL et al.. 2007. Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-derived growth factor receptor beta provides a dual mechanism of negative regulation.. J Biol Chem 282(40):29336-47 PMID: 17620338
- 4. Lu Z et al.. 2025. High Shear Stress-Induced Endothelial Piezo1 Downregulation Promotes Intracranial Aneurysm Formation via the PDGF-BB/PDGFRβ Paracrine Signaling Pathway.. CNS Neurosci Ther 31(12):e70715 PMID: 41457305
- 5. Bourgeade MF et al.. 1998. Myc is essential for transformation by TEL/platelet-derived growth factor receptor beta (PDGFRbeta).. Blood 91(9):3333-9 PMID: 9558390
- 6. Tomasovic A et al.. 2015. Sestrin 2 protein regulates platelet-derived growth factor receptor β (Pdgfrβ) expression by modulating proteasomal and Nrf2 transcription factor functions.. J Biol Chem 290(15):9738-52 PMID: 25716320
- 7. Guo Y et al.. 2013. Clinicopathological significance of platelet-derived growth factor B, platelet-derived growth factor receptor-β, and E-cadherin expression in gastric carcinoma.. Contemp Oncol (Pozn) 17(2):150-5 PMID: 23788982
- 8. Choudhury GG. 2001. Akt serine threonine kinase regulates platelet-derived growth factor-induced DNA synthesis in glomerular mesangial cells: regulation of c-fos AND p27(kip1) gene expression.. J Biol Chem 276(38):35636-43 PMID: 11470779
