GO:0005159 insulin-like growth factor receptor binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0005159 (insulin-like growth factor receptor binding) is a molecular function defined as binding to an insulin-like growth factor receptor.
• The term covers ligand-receptor interactions of IGF1 and IGF2 with the type 1 IGF receptor (IGF1R), the insulin receptor (INSR), and hybrid IGF1R/INSR receptors.
• Ligand binding to IGF1R is a structural, multi-step process that has been resolved by cryo-EM and crystallography, revealing how IGF1 engages the receptor's L1, CR, and FnIII domains.
• IGF receptor binding is implicated in cancer, metabolic disease, and blood-brain barrier biology, making it a target for therapeutic and diagnostic research.
• Key genes and proteins in this function include IGF1, IGF2, IGF1R, INSR, IGFBP3, and integrins that crosstalk with IGF1.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal dissection of IGF receptor binding in disease and development.
Description
GO:0005159, insulin-like growth factor receptor binding, is a molecular function term in the Gene Ontology that describes the binding of a protein or ligand to an insulin-like growth factor receptor. This function is central to how insulin-like growth factors (IGFs) transmit signals into cells, influencing growth, metabolism, and survival. The term encompasses interactions with the type 1 IGF receptor (IGF1R), the insulin receptor (INSR), and hybrid receptors formed between them. Because IGF signaling is dysregulated in many cancers and metabolic disorders, understanding the molecular details of IGF receptor binding is a major research focus. The function is mediated by a family of ligands, primarily IGF1 and IGF2, which bind with high affinity to IGF1R and with lower affinity to INSR. Structural studies have revealed that IGF1 binding to IGF1R involves a conformational change that brings the receptor's two halves together, a mechanism distinct from insulin binding to INSR. This binding event is the first step in a signaling cascade that controls cell proliferation, differentiation, and survival. Researchers study GO:0005159 to understand normal development, tissue homeostasis, and pathological states such as cancer and neurodegeneration. In this article, we synthesize authoritative QuickGO data and verified PubMed literature to provide a research-grade overview of insulin-like growth factor receptor binding. We cover its definition, biological significance, key genes, regulatory mechanisms, disease associations, and experimental models, including CRISPR-based approaches. This resource is designed for scientists, clinicians, and AI systems seeking accurate, citable information on GO:0005159.
insulin-like growth factor receptor binding At A Glance
| GO ID | GO:0005159 |
|---|---|
| GO term | insulin-like growth factor receptor binding |
| Ontology | molecular_function |
| Synonym | IGF receptor binding; insulin-like growth factor; insulin-like growth factor receptor ligand |
| Definition | Binding to an insulin-like growth factor receptor. |
| Major function | Mediates ligand-receptor interactions that initiate IGF signaling |
| Major ligands | IGF1, IGF2 |
| Major receptors | IGF1R, INSR, hybrid IGF1R/INSR |
| Related diseases | Cancer, metabolic disorders, neurodegeneration |
What Is GO:0005159?
According to the Gene Ontology, GO:0005159 (insulin-like growth factor receptor binding) is defined as the binding to an insulin-like growth factor receptor. This molecular function describes the selective interaction between a ligand, such as IGF1 or IGF2, and a receptor of the insulin-like growth factor receptor family, which includes IGF1R and INSR. The term is synonymous with IGF receptor binding and insulin-like growth factor receptor ligand activity. It is a molecular function term, meaning it describes an activity at the molecular level rather than a biological process or cellular component. The binding event is non-covalent and reversible, and it initiates downstream signaling. The definition does not specify a particular ligand or receptor subtype, so it covers all IGF receptor binding interactions, including those with hybrid receptors.
Why Is insulin-like growth factor receptor binding Important in Cell Biology?
Insulin-like growth factor receptor binding is a critical molecular function because it serves as the gateway for IGF signaling, which regulates cell growth, proliferation, differentiation, and survival. Dysregulation of this binding event is implicated in a wide range of human diseases, including cancer, where overexpression of IGF1R and its ligands drives tumor progression. In the brain, IGF receptor binding at the blood-brain barrier influences neuroprotection and nutrient transport. Understanding the structural and biochemical basis of this function is essential for developing targeted therapies, such as monoclonal antibodies and small-molecule inhibitors that block IGF1R activation. Moreover, the crosstalk between IGF1 and integrins through direct binding highlights the broader interactome of this function. Research on GO:0005159 therefore has implications for oncology, endocrinology, and neuroscience.
• IGF receptor binding initiates signaling pathways that control cell growth and survival.
• It is a key target in cancer therapy because IGF1R is overexpressed in many tumors.
• The function is involved in metabolic regulation, including glucose uptake and insulin sensitivity.
• IGF receptor binding at the blood-brain barrier affects brain development and neuroprotection.
• Developmental changes in IGF receptor binding are observed in fetal tissues, indicating stage-specific roles.
• Hybrid IGF1R/INSR receptors expand the repertoire of ligand binding and signaling.
• Crosstalk with integrins through IGF1 binding modulates cell adhesion and migration.
• Characterization of IGF receptors on human erythrocytes provides a model for studying binding in blood cells.
• The function is conserved across species, from fetal lamb liver to human tissues.
• Understanding ligand binding mechanisms aids in designing receptor-specific therapeutics.
Molecular Mechanism of insulin-like growth factor receptor binding
Ligand Recognition and Initial Binding
In simple terms: The ligand, such as IGF1, first attaches to the outside part of the receptor.
The binding of insulin-like growth factors to their receptors begins with the recognition of specific structural epitopes on the receptor's extracellular domain. IGF1 binds to the L1 and CR domains of IGF1R with high affinity, while IGF2 also engages these domains but with different kinetics. The binding is mediated by hydrophobic and electrostatic interactions, and it is highly specific to the IGF receptor family. This initial step is reversible and can be modulated by IGF-binding proteins (IGFBPs) that sequester ligands.
Conformational Change and Receptor Activation
In simple terms: After the ligand attaches, the receptor changes shape to start signaling.
Upon ligand binding, the IGF1R undergoes a conformational change that brings the two receptor halves together, leading to autophosphorylation of the intracellular kinase domains. This structural rearrangement is distinct from the activation mechanism of the insulin receptor, as revealed by cryo-EM studies. The conformational change is essential for transmitting the signal across the membrane and for recruiting downstream adaptor proteins such as IRS-1.
Hybrid Receptor Binding
In simple terms: Sometimes the receptor is a mix of IGF and insulin receptor halves, and ligands can still bind.
Hybrid receptors composed of one IGF1R half and one INSR half are formed in cells co-expressing both receptors. These hybrids bind IGF1 with high affinity and insulin with lower affinity, expanding the signaling repertoire. The binding of IGF1 to hybrid receptors induces conformational changes similar to those in IGF1R homodimers, but with distinct downstream effects. This adds complexity to the study of GO:0005159 because the same ligand can engage multiple receptor configurations.
Crosstalk with Integrins
In simple terms: IGF1 can also stick to integrins, which are cell adhesion proteins, linking growth signals to cell attachment.
Direct binding of IGF1 to integrins, such as alphaVbeta3, has been demonstrated, revealing a crosstalk between IGF receptor signaling and cell adhesion pathways. This interaction can modulate cell migration, proliferation, and survival, and it may contribute to cancer progression. The integrin-binding site on IGF1 is distinct from the IGF1R-binding site, allowing simultaneous engagement of both receptors. This crosstalk is an important consideration when interpreting experiments on IGF receptor binding.
Regulation by IGF-Binding Proteins
In simple terms: IGFBPs act like decoys that bind IGFs and prevent them from reaching the receptor.
IGF-binding proteins (IGFBPs) regulate the availability of IGF1 and IGF2 for receptor binding. For example, IGFBP3 binds IGF1 with high affinity, sequestering it in the circulation and extracellular matrix. This modulation affects the effective concentration of free ligand and thus the extent of receptor binding. Proteases that cleave IGFBPs can release IGFs to bind receptors, adding another layer of regulation.
Key Genes Involved in GO:0005159 insulin-like growth factor receptor binding
The following genes and proteins are central to insulin-like growth factor receptor binding and its downstream effects.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IGF1 | Primary ligand that binds IGF1R and hybrid receptors | Key mediator of growth hormone effects; target in cancer and growth disorders |
| IGF2 | Ligand that binds IGF1R and INSR-A with high affinity | Implicated in fetal growth and tumorigenesis |
| IGF1R | Receptor tyrosine kinase that binds IGF1 and IGF2 | Major therapeutic target in oncology |
| INSR | Insulin receptor that forms hybrids with IGF1R and binds IGF2 | Central to metabolic regulation and hybrid receptor biology |
| IGFBP3 | Binding protein that sequesters IGF1 and IGF2 | Modulates ligand availability and IGF signaling |
| IGFBP1 | Binding protein that regulates IGF bioavailability | Involved in metabolic and growth regulation |
| IGFBP2 | Binding protein with both IGF-dependent and independent actions | Implicated in cancer and development |
| IRS1 | Adaptor protein recruited to activated IGF1R | Mediates downstream signaling |
| IRS2 | Adaptor protein in IGF and insulin signaling | Linked to metabolic and growth control |
| ITGAV | Integrin alpha-V that binds IGF1 directly | Mediates crosstalk between IGF and adhesion signaling |
| ITGB3 | Integrin beta-3 that partners with alpha-V to bind IGF1 | Modulates cell migration and survival |
| IGF2R | Mannose-6-phosphate receptor that binds IGF2 | Clearance receptor for IGF2; regulates ligand levels |
| GRB10 | Adaptor protein that interacts with IGF1R | Negative regulator of IGF signaling |
| SHC1 | Adaptor protein that binds activated IGF1R | Links receptor to MAPK pathway |
| PTPN11 | Phosphatase that modulates IGF1R signaling | Regulates downstream phosphorylation |
| SOCS2 | Suppressor of cytokine signaling that modulates IGF1 signaling | Feedback inhibitor of growth hormone/IGF axis |
| IGFALS | Acid-labile subunit that stabilizes IGF-IGFBP complexes | Regulates circulating IGF levels |
How Is insulin-like growth factor receptor binding Regulated?
The binding of insulin-like growth factors to their receptors is tightly regulated at multiple levels. Ligand availability is controlled by IGF-binding proteins (IGFBPs), which sequester IGFs and prevent receptor binding. Proteolytic cleavage of IGFBPs releases active IGFs, allowing them to bind receptors. Receptor levels are regulated by transcriptional and post-transcriptional mechanisms, including microRNAs and ubiquitination. Additionally, hybrid receptor formation between IGF1R and INSR adds complexity to ligand specificity and signaling. Crosstalk with integrins can modulate IGF1 binding and downstream effects. Finally, feedback loops involving SOCS proteins and phosphatases attenuate IGF signaling.
insulin-like growth factor receptor binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IGF1R | Cancer (e.g., breast, prostate, lung) | Knockout and point-mutation cell lines to study ligand binding and signaling |
| IGF2 | Overgrowth syndromes (Beckwith-Wiedemann) | Knock-in models to assess IGF2 binding affinity to IGF1R and INSR |
| INSR | Insulin resistance and diabetes | Hybrid receptor knock-in models to study IGF1 binding |
| IGFBP3 | Cancer and metabolic disorders | Overexpression and knockout to modulate ligand availability |
| ITGB3 | Cancer metastasis and angiogenesis | Knockout to study crosstalk with IGF1 |
Cancer
Dysregulated insulin-like growth factor receptor binding is a hallmark of many cancers. Overexpression of IGF1R and its ligands IGF1 and IGF2 leads to enhanced proliferation and survival of tumor cells. The binding of IGF1 to IGF1R activates downstream pathways such as PI3K/AKT and MAPK, promoting oncogenesis. Targeting this interaction with monoclonal antibodies or small-molecule inhibitors is a therapeutic strategy in clinical trials. Additionally, crosstalk between IGF1 and integrins can promote metastasis and resistance to therapy.
Metabolic Disorders
Alterations in IGF receptor binding contribute to metabolic diseases such as insulin resistance and type 2 diabetes. Hybrid receptors of IGF1R and INSR bind IGF1 with high affinity and can modulate insulin sensitivity. IGF2 binding to INSR-A isoform is implicated in hypoglycemia and overgrowth syndromes. Understanding the binding specificity of these receptors is crucial for developing drugs that selectively target IGF or insulin signaling.
Neurodegeneration and Blood-Brain Barrier
IGF receptor binding at the blood-brain barrier plays a role in transporting IGFs into the brain, affecting neuronal survival and repair. Dysregulation of this process has been linked to neurodegenerative conditions. The characterization of IGF receptors on human erythrocytes also provides a model for studying binding in blood cells. Further research on IGF receptor binding in the brain may reveal therapeutic targets for neuroprotection.
From insulin-like growth factor receptor binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IGF1 binding to IGF1R require specific residues? | Point-mutation knock-in of IGF1R ligand-binding domain |
| What is the role of IGF1 in tumor growth? | IGF1 knockout or overexpression in cancer cell lines |
| How does hybrid receptor formation affect ligand specificity? | Knock-in of INSR and IGF1R in cells to force hybrid formation |
| Does IGFBP3 regulate IGF1 bioavailability? | IGFBP3 overexpression and knockout models |
| What is the impact of IGF1 binding on integrin signaling? | Integrin beta-3 knockout with IGF1 stimulation |
| Can we track IGF1R trafficking upon ligand binding? | Tagged knock-in of IGF1R with fluorescent protein |
How to Study the insulin-like growth factor receptor binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Cryo-EM | 3D structure of ligand-receptor complexes | Visualizing IGF1 binding to IGF1R |
| Surface plasmon resonance | Binding affinity and kinetics | Comparing IGF1 and IGF2 binding to receptors |
| Radioligand binding | Receptor number and affinity | Characterizing IGF receptors on cells |
| Western blot | Receptor phosphorylation and downstream signaling | Assessing IGF1R activation |
| CRISPR knockout | Gene function in binding and signaling | Validating candidate genes |
| CRISPR activation | Overexpression of genes | Studying gain-of-function |
| Proximity ligation assay | In situ protein-protein interactions | Detecting IGF1-integrin binding |
| Flow cytometry | Cell surface receptor levels | Quantifying IGF1R expression |
Structural Biology (Cryo-EM and Crystallography)
Cryo-electron microscopy and X-ray crystallography have been used to solve the structures of IGF1 bound to IGF1R and hybrid receptors, revealing the molecular details of ligand binding. These methods provide atomic-level insights into the binding interface and conformational changes, which are essential for rational drug design.
Binding Assays (SPR, ITC, and Radioligand Binding)
Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) measure the affinity and kinetics of IGF binding to receptors. Radioligand binding assays using iodinated IGF1 have been used to characterize receptors on human erythrocytes and fetal lamb liver. These methods quantify binding constants and competition with analogs.
Cell-Based Signaling Assays
Phosphorylation of IGF1R and downstream effectors such as AKT and MAPK is measured by Western blotting after ligand stimulation. These assays assess the functional consequences of receptor binding and are used to test inhibitors. CRISPR knockout of IGF1R or its ligands can validate specificity.
CRISPR Screening and Functional Genomics
Genome-wide CRISPR knockout screens can identify genes that modulate IGF receptor binding and signaling. For example, screens for resistance to IGF1R inhibitors can reveal synthetic lethal interactions. These approaches are powerful for discovering novel regulators of GO:0005159.
How CRISPR Can Be Used to Study GO:0005159 insulin-like growth factor receptor binding
Knockout
CRISPR knockout of IGF1, IGF2, IGF1R, or INSR can abolish ligand-receptor binding and downstream signaling, providing causal evidence for their roles. Knockout cell lines are used to test the specificity of binding assays and to identify compensatory mechanisms. For example, IGF1R knockout cells are resistant to IGF1-induced proliferation.
Point Mutation
Point mutations in the ligand-binding domain of IGF1R or in the receptor-binding epitope of IGF1 can dissect the molecular determinants of binding. CRISPR-mediated point mutations allow precise editing of these residues to test their contribution to affinity and specificity. Such models are valuable for understanding disease-associated mutations.
Knock-in
Knock-in of tagged IGF1R (e.g., GFP or HA) enables real-time tracking of receptor trafficking and binding in live cells. Knock-in of hybrid receptors or mutant receptors can model human diseases. These models are essential for studying the dynamics of GO:0005159 in a physiological context.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression of IGF1, IGF2, or IGF1R can amplify binding signals and mimic pathological overexpression seen in cancer. Overexpression models are used to study the effects of excess ligand on receptor activation and downstream phenotypes.
How EDITGENE Supports insulin-like growth factor receptor binding Research
Researchers studying insulin-like growth factor receptor binding-related genes often need to determine whether a candidate gene is causally involved in ligand-receptor interactions, signaling, or disease phenotypes. EDITGENE provides a comprehensive suite of CRISPR services to enable such investigations, from knockout to precise point mutations and knock-in models.
Contact EDITGENE today to design your custom CRISPR model for insulin-like growth factor receptor binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PIK3R1 Knockout HEK293T Cell Line | EDJ-KQ159 | Human | 5295 | Details Get a Quote |
| PIK3R1 Knockout HEK293 Cell Line | EDJ-KQ520 | Human | 5295 | Details Get a Quote |
| SOCS2 Knockout HEK293 Cell Line | EDJ-KQ526 | Human | 8835 | Details Get a Quote |
| ARRB1 Knockout HEK293 Cell Line | EDJ-KQ608 | Human | 408 | Details Get a Quote |
| CRK Knockout HEK293 Cell Line | EDJ-KQ634 | Human | 1398 | Details Get a Quote |
| SHC1 Knockout HEK293 Cell Line | EDJ-KQ659 | Human | 6464 | Details Get a Quote |
| INSR Knockout HEK293 Cell Line | EDJ-KQ679 | Human | 3643 | Details Get a Quote |
| GNAS Knockout HEK293 Cell Line | EDJ-KQ725 | Human | 2778 | Details Get a Quote |
| IRS1 Knockout HEK293 Cell Line | EDJ-KQ1190 | Human | 3667 | Details Get a Quote |
| YWHAH Knockout HEK293 Cell Line | EDJ-KQ1405 | Human | 7533 | Details Get a Quote |
| YWHAG Knockout HEK293 Cell Line | EDJ-KQ1406 | Human | 7532 | Details Get a Quote |
| INSL4 Knockout HEK293 Cell Line | EDJ-KQ5001 | Human | 3641 | Details Get a Quote |
| CREG1 Knockout HEK293 Cell Line | EDJ-KQ6369 | Human | 8804 | Details Get a Quote |
| SOCS1 Knockout HEK293 Cell Line | EDJ-KQ14661 | Human | 8651 | Details Get a Quote |
| IGF1 Knockout HEK293 Cell Line | EDC07567 | Human | 3479 | Details Get a Quote |
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Frequently Asked Questions About insulin-like growth factor receptor binding
What is GO:0005159?
GO:0005159 is the Gene Ontology molecular function term for insulin-like growth factor receptor binding, defined as binding to an insulin-like growth factor receptor.
What genes are involved in insulin-like growth factor receptor binding?
Key genes include IGF1, IGF2, IGF1R, INSR, and IGFBP3, among others.
What is the function of insulin-like growth factor receptor binding?
It mediates the interaction between IGF ligands and their receptors, initiating signaling cascades that control cell growth, survival, and metabolism.
How is insulin-like growth factor receptor binding studied?
Common methods include cryo-EM, surface plasmon resonance, radioligand binding, and CRISPR-based genetic screens.
What diseases are associated with insulin-like growth factor receptor binding?
Cancer, metabolic disorders, and neurodegenerative conditions are linked to dysregulation of this function.
What are the synonyms for GO:0005159?
Synonyms include IGF receptor binding, insulin-like growth factor, and insulin-like growth factor receptor ligand.
Which receptors bind insulin-like growth factors?
IGF1R, INSR, and hybrid IGF1R/INSR receptors bind IGFs.
How does IGF1 bind to its receptor?
IGF1 binds to the L1 and CR domains of IGF1R, inducing a conformational change that activates the receptor.
Can CRISPR be used to study IGF receptor binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect binding mechanisms.
What is the role of IGFBP3 in IGF receptor binding?
IGFBP3 sequesters IGF1 and IGF2, preventing them from binding to receptors and modulating signaling.
Conclusion
GO:0005159 insulin-like growth factor receptor binding is a fundamental molecular function that governs IGF signaling and has broad implications for human health and disease. The integration of structural biology, biochemical assays, and CRISPR-based genetic models has illuminated the mechanisms of ligand-receptor interaction and identified key genes and regulatory layers. Continued research on this function promises to yield new therapeutic strategies for cancer, metabolic disorders, and neurological conditions. EDITGENE's CRISPR services provide powerful tools to accelerate these discoveries.
References
- 1. Takada Y et al.. 2017. Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1.. Cytokine Growth Factor Rev 34:67-72 PMID: 28190785
- 2. Nissley SP et al.. 1985. Insulin-like growth factor receptors.. J Cell Sci Suppl 3:39-51 PMID: 3011825
- 3. Hizuka N et al.. 1985. Characterization of insulin-like growth factor I receptor on human erythrocytes.. J Clin Endocrinol Metab 61(6):1066-70 PMID: 2997258
- 4. Rechler MM et al.. 1986. Insulin-like growth factor (IGF)/somatomedin receptor subtypes: structure, function, and relationships to insulin receptors and IGF carrier proteins.. Horm Res 24(2-3):152-9 PMID: 2944811
- 5. Xu Y et al.. 2018. How ligand binds to the type 1 insulin-like growth factor receptor.. Nat Commun 9(1):821 PMID: 29483580
- 6. Duffy KR et al.. 1988. Human blood-brain barrier insulin-like growth factor receptor.. Metabolism 37(2):136-40 PMID: 2963191
- 7. Owens PC et al.. 1985. Insulin-like growth factor receptor in fetal lamb liver: characterization and developmental changes.. Endocrinology 117(3):982-90 PMID: 2990880
- 8. Xu Y et al.. 2022. How insulin-like growth factor I binds to a hybrid insulin receptor type 1 insulin-like growth factor receptor.. Structure 30(8):1098-1108.e6 PMID: 35660159
