GO:0043183 vascular endothelial growth factor receptor 1 binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0043183 describes the molecular function of binding to vascular endothelial growth factor receptor 1 (VEGFR-1, also known as Flt-1).
• VEGFR-1 is a dual regulator of angiogenesis, acting through both ligand sequestration and active signaling.
• Soluble VEGFR-1 (sFlt-1) binds VEGF and PlGF, modulating their availability and contributing to pathologies such as preeclampsia.
• Therapeutic targeting of VEGFR-1 binding is explored in cancer and retinal diseases using fusion polypeptides and neutralizing antibodies.
• Key genes involved include VEGFA, PGF, FLT1, and KDR, which are studied using knockout, knock-in, and overexpression models.
• CRISPR-based models enable precise interrogation of VEGFR-1 binding interfaces and downstream signaling in health and disease.
Description
Vascular endothelial growth factor receptor 1 binding (GO:0043183) is a molecular function defined as the binding to vascular endothelial growth factor receptor 1 (VEGFR-1), a receptor tyrosine kinase also known as Flt-1. This interaction is central to angiogenesis, where VEGFR-1 acts as a dual regulator by modulating ligand availability and initiating signaling cascades. Researchers study this binding event to understand how cells sense and respond to VEGF family ligands, particularly in vascular development and disease. The term encompasses interactions with both membrane-bound and soluble forms of VEGFR-1, which have distinct roles in physiology and pathology. Given its involvement in cancer, retinopathies, and preeclampsia, VEGFR-1 binding is a prime target for therapeutic intervention and a focus of intense biomedical research.
vascular endothelial growth factor receptor 1 binding At A Glance
| GO ID | GO:0043183 |
|---|---|
| GO term | vascular endothelial growth factor receptor 1 binding |
| Ontology | molecular_function |
| Synonym | Flt-1 binding, VEGFR 1 binding, VEGF receptor 1 binding |
| Major function | Binding to VEGFR-1 to modulate angiogenesis, vascular permeability, and cell survival |
| Definition | Binding to a vascular endothelial growth factor receptor 1. |
| Related genes | VEGFA, VEGFB, PGF, FLT1, KDR |
| Associated diseases | Cancer, preeclampsia, retinopathies, inflammatory disorders |
What Is GO:0043183?
GO:0043183 is defined as the binding to a vascular endothelial growth factor receptor 1. In other words, it is the molecular function of physically interacting with VEGFR-1 (Flt-1), a cell surface receptor for VEGF family ligands. This binding can occur between VEGFR-1 and its ligands (such as VEGFA, VEGFB, or PlGF) or between VEGFR-1 and other proteins that modulate its activity. The term is used to annotate gene products that directly bind to VEGFR-1, including growth factors, decoy receptors, and intracellular adaptor proteins.
Why Is vascular endothelial growth factor receptor 1 binding Important in Cell Biology?
VEGFR-1 binding is critically important because it governs fundamental processes in vascular biology, including angiogenesis, lymphangiogenesis, and vascular permeability. Dysregulation of this binding contributes to a wide range of diseases, from tumor progression to pregnancy complications such as preeclampsia. Understanding the molecular details of VEGFR-1 binding enables the design of targeted therapeutics, such as VEGF Trap and neutralizing antibodies, which are already used in clinical settings. Moreover, the dual role of VEGFR-1 as both a decoy and a signaling receptor makes its binding interactions a paradigm for studying context-dependent molecular functions.
• Regulates angiogenesis and vascular development.
• Modulates vascular permeability and inflammation.
• Involved in tumor angiogenesis and cancer progression.
• Implicated in preeclampsia via soluble VEGFR-1 (sFlt-1).
• Target for anti-angiogenic therapies in ophthalmology and oncology.
• Key to understanding ligand sequestration and signaling balance.
• Provides a model for studying receptor tyrosine kinase binding specificity.
• Enables development of fusion polypeptides and inhibitors.
What Happens During vascular endothelial growth factor receptor 1 binding?
Ligand recognition and binding
In simple terms: VEGFR-1 binds to VEGF family ligands like a lock and key.
VEGFR-1 (Flt-1) specifically binds to VEGF-A, VEGF-B, and PlGF through its extracellular immunoglobulin-like domains. This binding is high-affinity and can occur on the cell surface or in soluble form (sFlt-1). The interaction triggers conformational changes that may lead to receptor dimerization and activation, although VEGFR-1 has weaker kinase activity compared to VEGFR-2.
Receptor dimerization and signaling
In simple terms: When VEGFR-1 binds a ligand, it pairs up with another receptor to send signals inside the cell.
Ligand binding induces dimerization of VEGFR-1, leading to autophosphorylation of its intracellular kinase domain. This initiates downstream signaling pathways, including PI3K/AKT and MAPK, which regulate cell survival, migration, and gene expression. However, VEGFR-1 can also act as a decoy receptor, sequestering VEGF and preventing it from activating VEGFR-2.
Modulation by soluble VEGFR-1
In simple terms: A soluble form of VEGFR-1 can soak up VEGF like a sponge, controlling its availability.
Soluble VEGFR-1 (sFlt-1) is produced by alternative splicing and lacks the transmembrane and intracellular domains. It binds VEGF and PlGF with high affinity, reducing their free concentrations and thereby inhibiting angiogenesis. Elevated sFlt-1 levels are associated with preeclampsia, where it contributes to endothelial dysfunction.
Regulation of binding affinity and specificity
In simple terms: The strength and specificity of VEGFR-1 binding can be tuned by other proteins and post-translational modifications.
Neuropilins and heparan sulfate proteoglycans can enhance or modulate VEGFR-1 binding to its ligands. Additionally, alternative splicing and proteolytic cleavage generate receptor variants with different binding properties. These regulatory mechanisms fine-tune VEGFR-1 activity in different physiological contexts.
Key Genes Involved in GO:0043183 vascular endothelial growth factor receptor 1 binding
The following genes encode proteins that directly bind to or modulate VEGFR-1, playing key roles in angiogenesis and vascular biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Primary ligand for VEGFR-1; induces angiogenesis | Knockout causes embryonic lethality; studied in cancer and retinopathy |
| VEGFB | Ligand for VEGFR-1; regulates lipid metabolism and angiogenesis | Knockout models show metabolic phenotypes; less studied in cancer |
| PGF | Placental growth factor; binds VEGFR-1 and neuropilins | Implicated in preeclampsia and tumor angiogenesis |
| FLT1 | Encodes VEGFR-1; receptor tyrosine kinase | Knockout leads to vascular defects; target for CRISPR editing |
| KDR | VEGFR-2; co-receptor with VEGFR-1 | Competes for VEGF binding; key in angiogenesis |
| NRP1 | Neuropilin-1; enhances VEGFR-1 binding to VEGF | Modulates vascular development; studied in cancer |
| NRP2 | Neuropilin-2; co-receptor for VEGFR-1 | Involved in lymphangiogenesis |
| HSPG2 | Heparan sulfate proteoglycan; modulates ligand binding | Affects VEGF gradient formation |
| VEGFC | Ligand for VEGFR-2/3; may interact with VEGFR-1 | Studied in lymphangiogenesis |
| VEGFD | Ligand for VEGFR-3; potential VEGFR-1 binding | Less characterized |
| PLGF | Alternative name for PGF | See PGF |
| FLT4 | VEGFR-3; related receptor | Not a primary VEGFR-1 binder |
| GRB2 | Adaptor protein downstream of VEGFR-1 | Mediates signaling; studied in KO models |
| PIK3CA | PI3K subunit; downstream of VEGFR-1 | Involved in survival signaling |
| AKT1 | Kinase downstream of VEGFR-1 | Regulates cell survival |
| MAPK1 | ERK2; downstream of VEGFR-1 | Controls proliferation |
| SRC | Kinase modulating VEGFR-1 signaling | Studied in vascular permeability |
| PTPN11 | SHP-2; phosphatase regulating VEGFR-1 | Modulates signaling output |
How Is vascular endothelial growth factor receptor 1 binding Regulated?
VEGFR-1 binding is regulated at multiple levels, including ligand availability, receptor expression, alternative splicing, and post-translational modifications. Hypoxia induces VEGFA and VEGFR-1 expression via HIF-1α, enhancing binding under low oxygen conditions. Soluble VEGFR-1 (sFlt-1) acts as a decoy to sequester ligands, and its production is increased in preeclampsia. Additionally, neuropilins and heparan sulfate proteoglycans modulate binding affinity and specificity. Intracellular signaling downstream of VEGFR-1 is controlled by phosphatases such as SHP-2 and by endocytosis of the receptor-ligand complex.
vascular endothelial growth factor receptor 1 binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FLT1 | Preeclampsia, cancer, retinopathy | Knockout mice, sFlt-1 overexpression |
| VEGFA | Cancer, age-related macular degeneration | Conditional knockout, VEGF Trap |
| PGF | Preeclampsia, tumor angiogenesis | PGF knockout mice |
| KDR | Cancer, vascular anomalies | Kinase-dead knock-in |
| NRP1 | Cancer, cardiovascular disease | Neuropilin-1 knockout |
VEGFR-1 binding in cancer
In tumors, VEGFR-1 binding promotes angiogenesis, tumor growth, and metastasis. Cancer cells and stromal cells express VEGFR-1, and its activation by VEGF-A or PlGF stimulates survival and migration. Targeting VEGFR-1 binding with inhibitors or fusion polypeptides has shown anti-angiogenic effects in preclinical models.
VEGFR-1 binding in preeclampsia
Elevated levels of soluble VEGFR-1 (sFlt-1) in maternal circulation bind and sequester VEGF and PlGF, leading to endothelial dysfunction and preeclampsia. This highlights the pathological consequences of altered VEGFR-1 binding.
VEGFR-1 binding in retinal angiogenesis
VEGFR-1 signaling contributes to retinal angiogenesis and microinflammation, and its modulation is explored for treating retinopathies. Soluble VEGFR-1 can inhibit pathological neovascularization.
From vascular endothelial growth factor receptor 1 binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does VEGFR-1 binding mediate angiogenesis? | FLT1 knockout zebrafish or mice |
| What is the role of sFlt-1 in preeclampsia? | sFlt-1 overexpression in pregnant mice |
| Can VEGFR-1 binding be blocked therapeutically? | VEGF Trap or anti-VEGFR-1 antibodies in tumor xenografts |
| How does VEGFR-1 binding affect retinal microinflammation? | Retinal endothelial cell knockout of FLT1 |
| What are the signaling pathways downstream of VEGFR-1? | Point mutations in FLT1 kinase domain |
| How does ligand specificity affect VEGFR-1 binding? | Knock-in of VEGFB or PGF into VEGFA locus |
How to Study the vascular endothelial growth factor receptor 1 binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| SPR | Binding affinity and kinetics | Characterizing VEGFR-1 ligand interactions |
| Co-IP | Protein-protein interactions | Detecting VEGFR-1 binding partners |
| Phospho-proteomics | Signaling pathway activation | Mapping downstream events |
| CRISPR screen | Gene essentiality for binding | Identifying modulators of VEGFR-1 function |
| ELISA | Ligand concentration | Measuring sFlt-1 in preeclampsia |
| Immunofluorescence | Cellular localization | Visualizing VEGFR-1 binding in tissues |
| Flow cytometry | Cell surface binding | Quantifying VEGFR-1 expression |
| Western blot | Protein expression and phosphorylation | Validating signaling changes |
Surface plasmon resonance (SPR)
SPR measures real-time binding kinetics between VEGFR-1 and its ligands, providing affinity constants (KD) and association/dissociation rates. This method is used to characterize inhibitors and fusion proteins.
Co-immunoprecipitation (Co-IP)
Co-IP detects physical interactions between VEGFR-1 and binding partners in cell lysates, confirming binding in physiological contexts.
Phospho-proteomics
Mass spectrometry-based phosphoproteomics identifies downstream signaling events triggered by VEGFR-1 binding, revealing activated pathways.
CRISPR screening
Genome-wide CRISPR knockout screens can identify genes that modulate VEGFR-1 binding and downstream angiogenesis, uncovering novel regulators.
How CRISPR Can Be Used to Study GO:0043183 vascular endothelial growth factor receptor 1 binding
Knockout
CRISPR knockout of FLT1 or its ligands (VEGFA, PGF) eliminates VEGFR-1 binding, enabling studies of its role in angiogenesis and disease. Knockout models are used to assess the requirement for VEGFR-1 in developmental and pathological contexts.
Point Mutation
Point mutations in the ligand-binding domain of FLT1 or in VEGFA can disrupt specific binding interfaces, allowing structure-function analysis of VEGFR-1 binding. Such models help distinguish between signaling and decoy functions.
Knock-in
Knock-in of tagged or mutant versions of FLT1 (e.g., GFP-FLT1) enables real-time imaging of VEGFR-1 binding and trafficking in live cells. Knock-in of human FLT1 into mouse models facilitates testing of human-specific therapeutics.
Overexpression
Overexpression of soluble VEGFR-1 (sFlt-1) or its ligands using CRISPR activation or transgenic approaches models pathological states such as preeclampsia and tumor angiogenesis. This helps evaluate the therapeutic potential of modulating VEGFR-1 binding.
How EDITGENE Supports vascular endothelial growth factor receptor 1 binding Research
Researchers studying vascular endothelial growth factor receptor 1 binding-related genes often need to determine whether a candidate gene is causally involved in angiogenesis, vascular permeability, or disease progression. EDITGENE provides comprehensive CRISPR-based services to create precise cellular and animal models, enabling functional validation of VEGFR-1 binding mechanisms.
Contact EDITGENE today to design your custom CRISPR model for vascular endothelial growth factor receptor 1 binding research.
Frequently Asked Questions About vascular endothelial growth factor receptor 1 binding
What is vascular endothelial growth factor receptor 1 binding?
It is the molecular function of binding to VEGFR-1 (Flt-1), a receptor tyrosine kinase that regulates angiogenesis and vascular permeability.
What genes are involved in VEGFR-1 binding?
Key genes include VEGFA, VEGFB, PGF, FLT1, KDR, and NRP1, which encode ligands, receptors, and co-receptors.
What diseases are associated with VEGFR-1 binding?
Cancer, preeclampsia, retinopathies, and inflammatory disorders are linked to dysregulated VEGFR-1 binding.
How is VEGFR-1 binding studied?
Common methods include SPR, co-immunoprecipitation, phospho-proteomics, and CRISPR screens.
What is the role of soluble VEGFR-1 (sFlt-1)?
sFlt-1 binds VEGF and PlGF, acting as a decoy to inhibit angiogenesis; elevated levels cause preeclampsia.
Can VEGFR-1 binding be targeted therapeutically?
Yes, VEGF Trap and anti-VEGFR-1 antibodies are used to block binding in cancer and eye diseases.
What is the difference between VEGFR-1 and VEGFR-2?
VEGFR-1 (Flt-1) has higher affinity for VEGF but weaker kinase activity; VEGFR-2 (KDR) is the main angiogenic signaler.
How does CRISPR help study VEGFR-1 binding?
CRISPR enables knockout, knock-in, and point mutations to dissect binding interfaces and downstream effects.
What are the synonyms for GO:0043183?
Synonyms include Flt-1 binding, VEGFR 1 binding, and VEGF receptor 1 binding.
Why is VEGFR-1 binding important in cancer?
It promotes tumor angiogenesis and survival; inhibitors targeting this binding are in clinical use.
Conclusion
Vascular endothelial growth factor receptor 1 binding (GO:0043183) is a fundamental molecular function that orchestrates angiogenesis, vascular homeostasis, and disease. Its dual role as a signaling receptor and decoy highlights the complexity of VEGF biology. Continued research using advanced CRISPR models and binding assays will unravel new therapeutic opportunities for cancer, preeclampsia, and retinopathies.
References
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- 2. Shibuya M. 2006. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis.. Angiogenesis 9(4):225-30; discussion 231 PMID: 17109193
- 3. Kang MJ et al.. 2023. Vascular Endothelial Growth Factor Receptor 1 Targeting Fusion Polypeptides with Stimuli-Responsiveness for Anti-angiogenesis.. ACS Appl Mater Interfaces 15(27):32201-32214 PMID: 37384534
- 4. Papadopoulos N et al.. 2012. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab.. Angiogenesis 15(2):171-85 PMID: 22302382
- 5. Shibuya M. 2001. Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1).. Int J Biochem Cell Biol 33(4):409-20 PMID: 11312109
- 6. Failla CM et al.. 2018. Positive and Negative Regulation of Angiogenesis by Soluble Vascular Endothelial Growth Factor Receptor-1.. Int J Mol Sci 19(5) PMID: 29702562
- 7. Lacal PM et al.. 2018. Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors.. Pharmacol Res 136:97-107 PMID: 30170190
- 8. Levine RJ et al.. 2004. Circulating angiogenic factors and the risk of preeclampsia.. N Engl J Med 350(7):672-83 PMID: 14764923
