GO:0031995 insulin-like growth factor II binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031995 (insulin-like growth factor II binding) is a molecular function describing the selective binding of a protein to insulin-like growth factor II (IGF-II), a key growth factor involved in development and cancer.
• IGF-II binding proteins include the type 1 IGF receptor (IGF1R), the IGF-II/mannose-6-phosphate receptor (IGF2R), and a family of IGF-binding proteins (IGFBPs) that modulate IGF-II bioavailability.
• IGF-II binding is critical for normal growth and development, and its dysregulation is implicated in tumor progression, immunotherapy resistance, and extrapancreatic tumor hypoglycemia.
• Structural studies have revealed how IGF-II binds to IGF1R with high affinity, providing a template for understanding ligand-receptor interactions.
• Research tools such as radioligand binding assays, CRISPR knockout models, and structural biology are essential to dissect IGF-II binding mechanisms.
• EDITGENE offers CRISPR-based services to create knockout, point-mutation, knock-in, and overexpression cell models for studying IGF-II binding and its downstream effects.
Description
Insulin-like growth factor II (IGF-II) is a peptide hormone that plays a fundamental role in growth, development, and metabolism. The molecular function defined by GO:0031995, insulin-like growth factor II binding, refers to the specific interaction between a protein and IGF-II. This binding event is central to many physiological and pathological processes, as it determines the bioavailability, localization, and signaling activity of IGF-II. Researchers study this term to understand how IGF-II exerts its effects through receptors and binding proteins, and how disruptions in these interactions contribute to diseases such as cancer and hypoglycemia. The importance of IGF-II binding extends to therapeutic development, where targeting these interactions can modulate growth factor signaling. This article provides a comprehensive overview of the ontology, mechanisms, key genes, and research methodologies associated with GO:0031995, based on authoritative QuickGO data and verified PubMed literature.
insulin-like growth factor II binding At A Glance
| GO ID | GO:0031995 |
|---|---|
| GO term | insulin-like growth factor II binding |
| Ontology | molecular_function |
| Synonym | IGF-II binding |
| Definition | Binding to insulin-like growth factor II. |
| Major function | Mediates the interaction of proteins with IGF-II, influencing growth factor signaling, transport, and clearance. |
| Related ligands | IGF-II (insulin-like growth factor II) |
| Related receptors | IGF1R, IGF2R |
| Related binding proteins | IGFBP1-6, IGF2BP1-3 |
What Is GO:0031995?
GO:0031995, insulin-like growth factor II binding, is a molecular function defined as the selective interaction of a protein with insulin-like growth factor II (IGF-II). This binding is non-covalent and reversible, and it is essential for mediating the biological effects of IGF-II, including cell proliferation, differentiation, and survival.
Why Is insulin-like growth factor II binding Important in Cell Biology?
Insulin-like growth factor II binding is a fundamental molecular event that regulates the availability and activity of IGF-II, a growth factor critical for embryonic development and tissue homeostasis. Dysregulation of IGF-II binding is associated with a range of human diseases, including cancer, where IGF-II can promote tumor growth and immune evasion, and non-islet cell tumor hypoglycemia, a paraneoplastic syndrome caused by excessive IGF-II production. Understanding the molecular details of IGF-II binding is therefore essential for developing targeted therapies and diagnostic tools.
• IGF-II binding regulates growth and development by controlling IGF-II bioavailability and receptor activation.
• It is implicated in cancer progression, where IGF-II binding to IGF1R promotes proliferation and survival.
• IGF-II binding to IGF2R mediates lysosomal targeting and clearance of IGF-II, acting as a tumor suppressor pathway.
• Dysregulated IGF-II binding contributes to extrapancreatic tumor hypoglycemia.
• IGF-II binding proteins (IGFBPs) modulate IGF-II action and are potential therapeutic targets.
• Structural insights into IGF-II binding inform drug design for IGF1R inhibitors.
• CRISPR-based models enable functional dissection of IGF-II binding in disease contexts.
• Radioligand binding assays provide quantitative measures of IGF-II binding affinity.
• IGF-II binding is relevant to immunotherapy resistance in melanoma and other cancers.
• Understanding IGF-II binding can lead to biomarkers for cancer and metabolic disorders.
Molecular Mechanism of insulin-like growth factor II binding
Ligand Recognition and Binding Interface
In simple terms: This is how IGF-II physically docks onto a receptor or binding protein.
IGF-II binding is initiated by the specific recognition of IGF-II by its binding partners, such as IGF1R, IGF2R, or IGFBPs. Structural studies have elucidated the binding interface between IGF-II and the IGF1R ectodomain, revealing key residues that mediate high-affinity interaction. The binding involves multiple domains of the receptor and ligand, ensuring specificity and affinity.
Receptor Activation and Signaling
In simple terms: Once IGF-II binds, it can switch on cellular signals.
Upon binding to IGF1R, IGF-II induces receptor autophosphorylation and activation of downstream signaling pathways, including the MAPK and PI3K-Akt cascades, which promote cell growth and survival. This signaling is tightly regulated and can be hijacked in cancer cells to drive proliferation and immune evasion.
Modulation by IGF-Binding Proteins
In simple terms: IGFBPs act like chaperones that can either block or deliver IGF-II.
IGF-binding proteins (IGFBPs) bind IGF-II with high affinity, modulating its interaction with receptors. For example, IGFBP-2 and IGFBP-3 can sequester IGF-II, preventing receptor activation, while also potentially delivering IGF-II to specific tissues. The balance between free and bound IGF-II is critical for its biological activity.
Clearance and Lysosomal Targeting
In simple terms: The IGF2R acts as a scavenger that removes IGF-II from circulation.
The IGF-II/mannose-6-phosphate receptor (IGF2R) binds IGF-II and targets it to lysosomes for degradation, thereby regulating IGF-II levels. This function is important for controlling growth factor availability and is often lost in cancer due to IGF2R mutations or loss of heterozygosity.
Regulation of IGF-II Bioavailability
In simple terms: The amount of IGF-II that can bind is controlled by production and degradation.
IGF-II bioavailability is regulated at multiple levels, including transcription, mRNA stability, and proteolytic processing of pro-IGF-II. The E-domain of pro-IGF-II can be cleaved to generate bioactive fragments that may have distinct binding properties. Additionally, IGF-II binding to IGF2R and IGFBPs influences its half-life and tissue distribution.
Key Genes Involved in GO:0031995 insulin-like growth factor II binding
The following genes encode proteins that bind IGF-II or regulate its availability, and they are central to the study of GO:0031995.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IGF2 | Encodes IGF-II, the ligand for GO:0031995 | Overexpression in cancers, hypoglycemia; target for knockout and knock-in models |
| IGF1R | Receptor tyrosine kinase that binds IGF-II with high affinity | Mediates IGF-II signaling; structural studies, point mutations to disrupt binding |
| IGF2R | Mannose-6-phosphate receptor that binds IGF-II for lysosomal degradation | Tumor suppressor; knockout models show IGF-II accumulation |
| IGFBP1 | IGF-binding protein that modulates IGF-II action | Regulates IGF-II bioavailability; overexpression models |
| IGFBP2 | IGF-binding protein with high affinity for IGF-II | Biomarker in cancer; knockout and overexpression studies |
| IGFBP3 | Major circulating IGF-binding protein | Modulates IGF-II effects; knock-in models for variants |
| IGFBP4 | IGF-binding protein involved in development | Knockout models show growth defects |
| IGFBP5 | IGF-binding protein with roles in bone and cancer | Overexpression linked to tumor progression |
| IGFBP6 | IGF-binding protein that inhibits IGF-II signaling | Tumor suppressor candidate; knockout studies |
| IGF2BP1 | RNA-binding protein that regulates IGF2 mRNA | Affects IGF-II translation; CRISPR knockout to study post-transcriptional regulation |
| IGF2BP2 | RNA-binding protein involved in IGF2 mRNA stability | Associated with diabetes; knockout models |
| IGF2BP3 | Oncofetal RNA-binding protein | Promotes IGF-II expression; overexpression in cancers |
| INSR | Insulin receptor that can bind IGF-II with low affinity | Cross-reactivity with IGF-II; point mutations to alter specificity |
| INSR-A | Splice variant of INSR with higher affinity for IGF-II | Isoform-specific binding studies |
| IGFALS | Acid-labile subunit that stabilizes IGF-IGFBP complexes | Knockout models affect IGF-II half-life |
| PAPPA | Protease that cleaves IGFBP-3, releasing IGF-II | Regulates IGF-II bioavailability; knockout and overexpression models |
| PAPPA2 | Protease that cleaves IGFBP-5 | Modulates IGF-II action in tissues |
| STC1 | Stanniocalcin-1, binds IGF-II and inhibits its action | Potential tumor suppressor; knockout models |
How Is insulin-like growth factor II binding Regulated?
The binding of IGF-II to its partners is regulated by the abundance of both ligand and receptor, as well as by IGF-binding proteins (IGFBPs) that compete for IGF-II binding. Proteases such as PAPPA and PAPPA2 cleave IGFBPs, releasing IGF-II to interact with receptors. Additionally, IGF2R acts as a clearance receptor, reducing IGF-II availability. Post-translational modifications of IGF-II, such as glycosylation, can also influence its binding affinity. Hormonal factors, including growth hormone and insulin, regulate IGF-II expression and secretion, indirectly affecting binding.
insulin-like growth factor II binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IGF2 | Cancer, hypoglycemia, overgrowth syndromes | Knockout, overexpression, point mutation |
| IGF1R | Cancer, growth retardation | Knockout, point mutation, knock-in |
| IGF2R | Cancer, developmental defects | Knockout, overexpression |
| IGFBP2 | Cancer, metabolic disorders | Knockout, overexpression |
| INSR | Diabetes, insulin resistance | Point mutation, knockout |
Cancer and Immunoevasion
IGF-II binding to IGF1R promotes tumor cell proliferation, survival, and metastasis. Recent studies have shown that IGF-II produced by fibroblasts in the tumor microenvironment drives immunoevasion and resistance to immunotherapy in melanoma. Targeting IGF-II binding or its downstream signaling could overcome resistance.
Non-Islet Cell Tumor Hypoglycemia
Excessive production of IGF-II by tumors can lead to non-islet cell tumor hypoglycemia (NICTH), a paraneoplastic syndrome characterized by low blood glucose. The hypoglycemia is caused by IGF-II binding to insulin receptors and IGF1R, leading to increased glucose uptake and inhibition of gluconeogenesis.
Developmental Disorders
IGF-II binding is critical for normal embryonic growth. Disruptions in IGF-II binding, due to mutations in IGF2 or IGF1R, can result in growth retardation and developmental syndromes. The IGF2R also plays a role in placental development and fetal growth.
Metabolic Disorders
Alterations in IGF-II binding have been linked to insulin resistance and type 2 diabetes. IGF-II can cross-react with insulin receptor isoforms, affecting glucose metabolism. IGF2BP2 variants are associated with increased risk of type 2 diabetes.
From insulin-like growth factor II binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IGF-II binding to IGF1R drive tumor growth? | IGF1R knockout cancer cell lines |
| What is the affinity of IGF-II for mutant IGF1R? | Point-mutation knock-in of IGF1R |
| How does IGF2R loss affect IGF-II levels? | IGF2R knockout cells |
| Can IGFBP-3 inhibit IGF-II signaling? | IGFBP-3 overexpression |
| What is the role of IGF2BP1 in IGF-II translation? | IGF2BP1 knockout and tagged knock-in |
| Does PAPPA cleavage regulate IGF-II bioavailability? | PAPPA knockout and overexpression |
How to Study the insulin-like growth factor II binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radioligand binding assay | Binding affinity (Kd) and kinetics | Characterize IGF-II binding to receptors/IGFBPs |
| Surface plasmon resonance | Real-time binding kinetics | Measure IGF-II interactions with immobilized proteins |
| Cryo-EM | 3D structure of binding complexes | Visualize IGF-II-IGF1R interface |
| CRISPR knockout | Loss-of-function effects | Determine gene requirement for IGF-II binding |
| CRISPR knock-in | Introduction of specific mutations | Study point mutations affecting binding |
| Co-immunoprecipitation | Protein-protein interactions | Identify novel IGF-II binding partners |
| RNA-seq | Transcriptional changes | Assess downstream effects of IGF-II binding |
| Western blot | Protein expression and phosphorylation | Validate signaling activation upon IGF-II binding |
Radioligand Binding Assays
Radioligand binding assays using iodinated IGF-II are a classic method to measure binding affinity and kinetics for receptors and IGFBPs. These assays can be adapted for high-throughput screening of compounds that modulate IGF-II binding.
Structural Biology (Cryo-EM, X-ray Crystallography)
Structural studies, such as the cryo-EM structure of the IGF-II-IGF1R complex, provide atomic-level details of the binding interface. These insights are invaluable for designing inhibitors or engineering binding proteins with altered specificity.
CRISPR-Cas9 Genome Editing
CRISPR knockout, knock-in, and point-mutation models allow functional dissection of genes involved in IGF-II binding. For example, knocking out IGF1R or IGF2R can reveal their roles in IGF-II-mediated signaling and clearance.
Proteomics and Immunoprecipitation
Co-immunoprecipitation coupled with mass spectrometry can identify novel IGF-II binding proteins and characterize complexes. This approach can uncover tissue-specific binding partners and post-translational modifications.
How CRISPR Can Be Used to Study GO:0031995 insulin-like growth factor II binding
Knockout
CRISPR knockout of genes encoding IGF-II binding proteins (e.g., IGF1R, IGF2R, IGFBPs) enables researchers to study loss-of-function phenotypes, such as altered cell proliferation, migration, and signaling. For instance, IGF1R knockout abolishes IGF-II-induced AKT phosphorylation.
Point Mutation
Introducing point mutations in the binding interface of IGF1R or IGF2R can precisely dissect the contribution of specific residues to IGF-II binding affinity and specificity. This approach is useful for validating structural predictions.
Knock-in
Knock-in of tagged versions of IGF-II binding proteins (e.g., GFP or HA tags) allows for live-cell imaging and proteomic analysis of binding dynamics. Knock-in of disease-associated mutations can model human disorders.
Overexpression
Overexpression of IGF-II or its binding proteins using CRISPR activation or lentiviral vectors can mimic pathological states, such as cancer or hypoglycemia, and help identify downstream effectors.
How EDITGENE Supports insulin-like growth factor II binding Research
Researchers studying insulin-like growth factor II binding-related genes often need to determine whether a candidate gene is causally involved in IGF-II binding and its downstream biology. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for insulin-like growth factor II binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| INSR Knockout HEK293 Cell Line | EDJ-KQ679 | Human | 3643 | Details Get a Quote |
| IGF2R Knockout HEK293 Cell Line | EDJ-KQ2786 | Human | 3482 | Details Get a Quote |
| IGFBP3 Knockout HEK293 Cell Line | EDJ-KQ3460 | Human | 3486 | Details Get a Quote |
| IGFBP1 Knockout HEK293 Cell Line | EDJ-KQ3865 | Human | 3484 | Details Get a Quote |
| IGFBP2 Knockout HEK293 Cell Line | EDJ-KQ4976 | Human | 3485 | Details Get a Quote |
| IGFBP4 Knockout HEK293 Cell Line | EDJ-KQ4978 | Human | 3487 | Details Get a Quote |
| IGFBP5 Knockout HEK293 Cell Line | EDJ-KQ4979 | Human | 3488 | Details Get a Quote |
| IGFBP6 Knockout HEK293 Cell Line | EDJ-KQ4981 | Human | 3489 | Details Get a Quote |
| INSR Knockout A-549 Cell Line | EDJ-KQ19214 | Human | 3643 | Details Get a Quote |
| INSR Knockout HCT 116 Cell Line | EDJ-KQ19215 | Human | 3643 | Details Get a Quote |
| INSR Knockout HeLa Cell Line | EDJ-KQ19216 | Human | 3643 | Details Get a Quote |
| IGFBP3 Knockout A-549 Cell Line | EDJ-KQ25206 | Human | 3486 | Details Get a Quote |
| IGFBP3 Knockout HCT 116 Cell Line | EDJ-KQ25207 | Human | 3486 | Details Get a Quote |
| IGFBP1 Knockout HeLa Cell Line | EDJ-KQ26061 | Human | 3484 | Details Get a Quote |
| IGF2R Knockout A-549 Cell Line | EDJ-KQ23707 | Human | 3482 | Details Get a Quote |
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Frequently Asked Questions About insulin-like growth factor II binding
What is GO:0031995?
GO:0031995 is the Gene Ontology term for insulin-like growth factor II binding, a molecular function describing the binding of a protein to IGF-II.
What genes are involved in insulin-like growth factor II binding?
Key genes include IGF2 (encoding IGF-II), IGF1R, IGF2R, and the IGFBP family (IGFBP1-6).
How does IGF-II bind to its receptor?
IGF-II binds to the extracellular domain of IGF1R, inducing receptor dimerization and autophosphorylation, which activates downstream signaling.
What is the role of IGF2R in IGF-II binding?
IGF2R binds IGF-II and targets it to lysosomes for degradation, thereby regulating IGF-II levels.
What diseases are associated with IGF-II binding?
Dysregulated IGF-II binding is linked to cancer, non-islet cell tumor hypoglycemia, and developmental disorders.
How can I study IGF-II binding in the lab?
Common methods include radioligand binding assays, surface plasmon resonance, and CRISPR-based gene editing.
What CRISPR models are available for IGF-II binding research?
Knockout, point mutation, knock-in, and overexpression models can be generated for genes like IGF1R and IGF2R.
What is the affinity of IGF-II for IGF1R?
IGF-II binds IGF1R with high affinity, though slightly lower than IGF-I; structural studies have revealed the binding interface.
Can IGF-II binding be targeted therapeutically?
Yes, antibodies and small molecules that block IGF-II binding to IGF1R are under investigation for cancer therapy.
What is the difference between IGF-II binding and IGF-I binding?
Both IGF-I and IGF-II bind IGF1R, but with different affinities and tissue-specific effects; IGF-II also binds IGF2R, which IGF-I does not.
Conclusion
Insulin-like growth factor II binding (GO:0031995) is a critical molecular function that governs the biological actions of IGF-II in development, metabolism, and disease. Understanding the structural and functional details of IGF-II binding has profound implications for cancer therapy, metabolic disorders, and growth regulation. With advanced CRISPR tools and bioinformatics, researchers can now dissect these interactions with unprecedented precision. EDITGENE is committed to supporting this research through customized cell models and screening services.
References
- 1. Song D et al.. 2024. Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy.. J Clin Invest 134(22) PMID: 39545420
- 2. Zapf J. 1994. Role of insulin-like growth factor II and IGF binding proteins in extrapancreatic tumor hypoglycemia.. Horm Res 42(1-2):20-6 PMID: 7525443
- 3. Gammeltoft S et al.. 1991. Insulin-like growth factor II: complexity of biosynthesis and receptor binding.. Adv Exp Med Biol 293:31-44 PMID: 1722620
- 4. Le Roith D. 1999. Insulin-like growth factor.. Horm Metab Res 31(2-3):41-2 PMID: 10226779
- 5. Xu Y et al.. 2020. How IGF-II Binds to the Human Type 1 Insulin-like Growth Factor Receptor.. Structure 28(7):786-798.e6 PMID: 32459985
- 6. Kiess W et al.. 1994. Insulin-like growth factor II (IGF-II) and the IGF-II/mannose-6-phosphate receptor: the myth continues.. Horm Res 41 Suppl 2:66-73 PMID: 8088706
- 7. van Doorn J. 2020. Insulin-like growth factor-II and bioactive proteins containing a part of the E-domain of pro-insulin-like growth factor-II.. Biofactors 46(4):563-578 PMID: 32026557
- 8. Potalitsyn P et al.. 2020. A radioligand binding assay for the insulin-like growth factor 2 receptor.. PLoS One 15(9):e0238393 PMID: 32877466
