GO:0043567 regulation of insulin-like growth factor receptor signaling pathway: Signaling Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0043567 describes any process that modulates the frequency, rate or extent of insulin-like growth factor receptor signaling, a central growth-control axis in metazoans.
• The pathway is initiated when IGF1 or IGF2 ligands bind IGF1R, a receptor tyrosine kinase that autophosphorylates and recruits IRS adaptors and Shc.
• Regulation occurs at multiple levels: ligand bioavailability via IGFBPs, receptor abundance and trafficking, phosphatase-mediated dephosphorylation, and downstream feedback through mTOR and ERK.
• Dysregulated IGF receptor signaling is implicated in hepatocellular carcinoma, non-small cell lung cancer, Alzheimer's disease, chronic migraine, and metabolic disorders.
• Key experimental models include IGF1R knockout and point-mutant knock-in cells, tagged IGF1R knock-ins, and IGF1/IGF2 overexpression systems.
• CRISPR-based knockout, point mutation, knock-in and overexpression platforms allow causal dissection of GO:0043567 regulators in isogenic backgrounds.
Description
GO:0043567, regulation of insulin-like growth factor receptor signaling pathway, is a biological process ontology term that captures any process modulating the frequency, rate or extent of signaling through insulin-like growth factor receptors. The insulin-like growth factor (IGF) system comprises the ligands IGF1 and IGF2, the receptors IGF1R and IGF2R, and a family of IGF-binding proteins (IGFBPs) that control ligand availability. Because IGF receptor signaling governs cell proliferation, survival, differentiation, and metabolism, its regulation is essential for normal development and tissue homeostasis. Researchers study GO:0043567 to understand how growth signals are tuned in physiology and how their dysregulation contributes to cancer, neurodegeneration, and metabolic disease. The term is deliberately broad: it includes ligand-dependent and ligand-independent modulation, receptor trafficking, post-translational modifications, and downstream feedback loops that adjust pathway output. This article synthesizes authoritative QuickGO annotation and verified PubMed literature to provide a research-grade overview of GO:0043567, its molecular players, disease relevance, and the CRISPR-based methods used to interrogate it.
regulation of insulin-like growth factor receptor signaling pathway At A Glance
| GO ID | GO:0043567 |
|---|---|
| GO term | regulation of insulin-like growth factor receptor signaling pathway |
| Ontology | biological_process |
| Synonym | regulation of IGF receptor signaling pathway; regulation of IGF receptor signalling pathway; regulation of insulin-like growth factor receptor signalling pathway |
| Major function | Modulates the frequency, rate or extent of IGF receptor signaling, thereby controlling proliferation, survival, differentiation and metabolism |
| Key ligands | IGF1, IGF2, and insulin at high concentrations |
| Key receptors | IGF1R (receptor tyrosine kinase), IGF2R/mannose-6-phosphate receptor |
| Key adaptors | IRS1, IRS2, Shc, Grb2, PI3K regulatory subunits |
| Major downstream cascades | PI3K-AKT-mTOR and RAS-RAF-MEK-ERK |
| Negative regulators | IGFBPs, PTEN, phosphatases such as PTP1B, SOCS proteins, and receptor ubiquitination |
What Is GO:0043567?
According to the Gene Ontology, GO:0043567 (regulation of insulin-like growth factor receptor signaling pathway) is defined as any process that modulates the frequency, rate or extent of insulin-like growth factor receptor signaling. In practical terms, it encompasses all molecular events that set the gain, duration, or spatial range of IGF1R/IGF2R signal transduction, including changes in ligand availability, receptor expression, receptor phosphorylation status, adaptor protein recruitment, and negative feedback. The term is a parent for more specific child terms such as positive regulation and negative regulation of IGF receptor signaling, and it is used to annotate gene products that act upstream or downstream of the receptor to tune pathway activity.
Why Is regulation of insulin-like growth factor receptor signaling pathway Important in Cell Biology?
GO:0043567 is important because IGF receptor signaling is a fundamental growth-control axis whose output must be tightly regulated for normal development and tissue repair, while its dysregulation drives cancer, neurodegeneration, and metabolic disease. Understanding how the pathway is modulated at the ligand, receptor, and post-receptor levels provides mechanistic insight into disease and identifies candidate targets for therapeutic intervention.
• Controls cell proliferation and survival, making it central to tissue growth and regeneration.
• Regulates glucose uptake and metabolism, linking IGF signaling to metabolic homeostasis.
• Is frequently hyperactivated in hepatocellular carcinoma through IGF2 reactivation.
• Plays context-dependent roles in non-small cell lung cancer, where IGF axis components can promote or restrain tumor growth.
• Contributes to Alzheimer's disease pathophysiology and is explored as a therapeutic target.
• Is implicated in chronic migraine through IGF1/IGF1R-dependent pain and autophagic dysfunction.
• Serves as a brain-body connector integrating systemic metabolic status with neural function.
• Provides a model for studying evolutionarily conserved growth regulation across vertebrates, including fish.
• Offers druggable nodes (IGF1R, IGF ligands, IGFBPs) for oncology and neurology.
• Enables CRISPR-based causal genetics of pathway regulators in isogenic cell models.
What Happens During regulation of insulin-like growth factor receptor signaling pathway?
Ligand availability and IGFBP modulation
In simple terms: Before the signal reaches the receptor, the amount of free IGF ligand is controlled by binding proteins.
The IGF system includes six high-affinity IGF-binding proteins (IGFBP1-6) that sequester IGF1 and IGF2 in the extracellular space and modulate their access to IGF1R. Proteases that cleave IGFBPs can release active ligand, while changes in IGFBP expression alter the effective concentration of IGFs. This ligand-buffering step is a primary point of regulation within GO:0043567, because it sets the frequency and extent of receptor activation without changing receptor levels.
Receptor activation and autophosphorylation
In simple terms: When IGF ligand binds IGF1R, the receptor switches on by adding phosphate groups to itself.
IGF1R is a disulfide-linked homodimeric receptor tyrosine kinase; ligand binding induces a conformational change that activates its intrinsic kinase activity and triggers trans-autophosphorylation of tyrosine residues in the juxtamembrane and kinase domains. These phosphotyrosines serve as docking sites for adaptor proteins, including IRS1/2 and Shc, which propagate the signal. Regulation of this step includes receptor glycosylation, trafficking to the plasma membrane, and ligand-independent activation mechanisms.
Adaptor recruitment and downstream cascade activation
In simple terms: Docking proteins assemble on the active receptor and switch on two major growth cascades.
Phosphorylated IRS1/2 recruit the p85 regulatory subunit of PI3K, leading to AKT activation and mTOR-dependent growth and survival signaling, while Shc-Grb2-SOS complexes activate the RAS-RAF-MEK-ERK cascade. The balance between these branches determines cellular outcomes such as proliferation, differentiation, or metabolic adaptation. Regulation of GO:0043567 therefore includes modulation of adaptor expression, phosphorylation, and degradation.
Negative feedback and termination
In simple terms: The cell uses brakes, such as phosphatases and feedback loops, to stop the growth signal.
Pathway output is restrained by tyrosine phosphatases (for example PTP1B), by SOCS proteins that target IRS for degradation, and by mTOR/S6K-mediated negative feedback phosphorylation of IRS1. Receptor ubiquitination and endocytic trafficking also attenuate signaling by routing IGF1R to degradation or recycling compartments. These termination mechanisms are integral to GO:0043567 because they determine signal duration and prevent sustained hyperactivation.
Crosstalk with insulin and other growth factor pathways
In simple terms: IGF receptors share components with insulin signaling, so the two systems influence each other.
IGF1R and the insulin receptor (INSR) can form hybrid receptors, and both converge on IRS-PI3K-AKT signaling, creating opportunities for crosstalk and compensatory activation. Regulation of IGF receptor signaling therefore includes modulation by insulin levels, hybrid receptor formation, and shared negative regulators such as PTEN. This crosstalk is relevant to metabolic disease and to resistance to IGF1R-targeted therapies.
Key Genes Involved in GO:0043567 regulation of insulin-like growth factor receptor signaling pathway
The following genes and proteins are central players in the regulation of insulin-like growth factor receptor signaling (GO:0043567), spanning ligands, receptors, adaptors, downstream kinases, and negative regulators.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IGF1 | Primary ligand activating IGF1R | Knockout and overexpression models for growth and metabolism studies |
| IGF2 | Fetal growth ligand; reactivated in tumors | Implicated in hepatocellular carcinoma and overgrowth syndromes |
| IGF1R | Receptor tyrosine kinase initiating the pathway | Central target for knockout, point mutation, and knock-in studies |
| IGF2R | Mannose-6-phosphate receptor that clears IGF2 | Regulates ligand availability and tumor suppression |
| INSR | Insulin receptor forming hybrids with IGF1R | Crosstalk studies in metabolic and cancer models |
| IRS1 | Adaptor recruiting PI3K to activated receptor | Phosphorylation and degradation studies |
| IRS2 | Adaptor with overlapping and distinct roles from IRS1 | Knockout models for growth and glucose homeostasis |
| SHC1 | Adaptor linking receptor to RAS-MAPK | Mechanistic studies of ERK activation |
| PIK3CA | Catalytic subunit of PI3K | Downstream effector in AKT signaling |
| AKT1 | Serine/threonine kinase promoting survival | Readout of pathway activity |
| MTOR | Kinase integrating growth and nutrient signals | Feedback regulation of IRS and pathway tuning |
| PTEN | Lipid phosphatase opposing PI3K | Negative regulator frequently lost in cancer |
| IGFBP3 | Binding protein sequestering IGF ligands | Modulates ligand bioavailability |
| IGFBP5 | Binding protein with context-dependent effects | Studied in cancer and development |
| PTPN1 | Protein tyrosine phosphatase 1B dephosphorylating receptor | Negative regulation of IGF and insulin signaling |
| SOCS2 | Suppressor of cytokine signaling targeting IRS | Feedback inhibition studies |
| GRB2 | Adaptor coupling Shc to SOS | MAPK activation studies |
How Is regulation of insulin-like growth factor receptor signaling pathway Regulated?
Regulation of IGF receptor signaling is multi-layered. At the ligand level, IGFBPs and IGF2R control free IGF concentrations. At the receptor level, expression, glycosylation, trafficking, and phosphatase-mediated dephosphorylation set sensitivity. Downstream, mTOR and S6K exert negative feedback on IRS1, while PTEN and SOCS proteins dampen PI3K-AKT output. Crosstalk with insulin receptors and other growth factor pathways further shapes the net signal, and these regulatory nodes are frequent targets of CRISPR interrogation.
regulation of insulin-like growth factor receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IGF2 | Hepatocellular carcinoma | IGF2 overexpression in hepatocyte cell lines and xenografts |
| IGF1R | Non-small cell lung cancer | IGF1R knockout and point-mutant lung cancer cells |
| IGF1 | Alzheimer's disease | Neuronal IGF1 overexpression or knockout models |
| IGF1R | Chronic migraine | IGF1R knockdown in mouse trigeminal ganglion models |
| IGF1R | Metabolic and growth disorders | Isogenic IGF1R knock-in cell lines |
IGF receptor signaling in hepatocellular carcinoma
Reactivation of the IGF2 signaling pathway is a recognized feature of human hepatocellular carcinoma, where fetal IGF2 expression re-emerges and drives proliferation through IGF1R. This illustrates how loss of normal regulation of GO:0043567 can contribute to tumorigenesis, and it supports targeting the IGF axis in liver cancer research.
IGF axis in non-small cell lung cancer
The IGF axis plays different roles in non-small cell lung cancer, with evidence for both tumor-promoting and context-dependent effects of IGF1R and its ligands. This heterogeneity underscores the importance of understanding pathway regulation when designing IGF1R-directed strategies.
IGF signaling in Alzheimer's disease
IGF signaling has been implicated in Alzheimer's disease pathophysiology, and therapeutic strategies targeting this pathway are under investigation. Because IGF receptors support neuronal survival and metabolic function, their regulation is relevant to neurodegeneration.
IGF1/IGF1R in chronic migraine
In a nitroglycerin-induced chronic migraine mouse model, targeting IGF1/IGF1R signaling relieved pain and autophagic dysfunction, linking regulation of IGF receptor signaling to headache biology.
From regulation of insulin-like growth factor receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of IGF1R abolish pathway output? | IGF1R knockout cell line |
| Does a specific phosphorylation site control signaling? | IGF1R point-mutant knock-in |
| How does tagged IGF1R behave in live cells? | Tagged IGF1R knock-in |
| Does IGF2 overexpression drive proliferation? | IGF2 overexpression cell model |
| Which adaptor is required for AKT activation? | IRS1 or IRS2 knockout |
| Can negative regulators be identified genome-wide? | CRISPR library screening |
How to Study the regulation of insulin-like growth factor receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Phospho-IGF1R immunoblot | Receptor autophosphorylation | Pathway activation after ligand stimulation |
| RNA-seq | Transcript levels of IGF axis genes | Perturbation response profiling |
| Proteomics | Protein abundance and modifications | Adaptor and feedback protein analysis |
| Live-cell imaging | Receptor trafficking dynamics | Tagged IGF1R knock-in studies |
| Proliferation assay | Cell growth rate | Functional consequence of pathway modulation |
| Apoptosis assay | Cell survival | Downstream AKT-dependent phenotypes |
| CRISPR library screen | Genes affecting pathway output | Genome-wide regulator discovery |
| Bioinformatics pathway analysis | Enrichment of IGF-related signatures | Interpretation of omics datasets |
Phospho-proteomics and receptor activation assays
Immunoprecipitation of IGF1R followed by phosphotyrosine immunoblotting or mass spectrometry measures receptor autophosphorylation and adaptor recruitment, providing direct readouts of pathway activation.
Transcriptomic and proteomic profiling
RNA-seq and quantitative proteomics can quantify expression changes in IGF ligands, receptors, IGFBPs, and downstream targets after genetic perturbation, revealing how regulators of GO:0043567 reshape the cellular program.
Live-cell imaging of receptor trafficking
Tagged IGF1R knock-in cells enable fluorescence imaging of receptor internalization, recycling, and degradation, which are key regulatory steps in GO:0043567.
Functional assays for proliferation and survival
Proliferation, apoptosis, and colony-formation assays link molecular changes in IGF receptor signaling to cellular phenotypes relevant to cancer and development.
How CRISPR Can Be Used to Study GO:0043567 regulation of insulin-like growth factor receptor signaling pathway
Knockout
CRISPR knockout of IGF1R, IGF1, IGF2, IRS1, or IRS2 creates isogenic cell lines that test the requirement of each component for GO:0043567 output, using phospho-AKT and proliferation as readouts.
Point Mutation
Point mutation of specific IGF1R tyrosine residues or kinase-domain residues via CRISPR base editing or HDR allows dissection of phosphorylation-dependent signaling and drug resistance without confounding expression changes.
Knock-in
Knock-in of epitope or fluorescent tags at the endogenous IGF1R locus enables tracking of receptor localization, trafficking, and interactome under native regulatory control.
Overexpression
CRISPR-mediated overexpression of IGF2 or IGF1 using safe-harbor integration models ligand-driven hyperactivation, as seen in hepatocellular carcinoma and other diseases.
How EDITGENE Supports regulation of insulin-like growth factor receptor signaling pathway Research
Researchers studying regulation of insulin-like growth factor receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway output or is merely correlated with it. EDITGENE provides the CRISPR tools and cell models required to move from association to causation in isogenic backgrounds.
Contact EDITGENE today to design your custom CRISPR model for regulation of insulin-like growth factor receptor signaling pathway research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| 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 |
| ZFAND2B Knockout HEK293 Cell Line | EDJ-KQ9248 | Human | 130617 | 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 |
| IGFBP3 Knockout HeLa Cell Line | EDJ-KQ23828 | Human | 3486 | Details Get a Quote |
| IGFBP1 Knockout A-549 Cell Line | EDJ-KQ24704 | Human | 3484 | Details Get a Quote |
| IGFBP2 Knockout HCT 116 Cell Line | EDJ-KQ26642 | Human | 3485 | Details Get a Quote |
| IGFBP6 Knockout HCT 116 Cell Line | EDJ-KQ26650 | Human | 3489 | Details Get a Quote |
| IGFBP2 Knockout A-549 Cell Line | EDJ-KQ27863 | Human | 3485 | Details Get a Quote |
Displaying Records 1 To 15 Of 28 Records
Frequently Asked Questions About regulation of insulin-like growth factor receptor signaling pathway
What is GO:0043567?
GO:0043567 is the Gene Ontology term for regulation of insulin-like growth factor receptor signaling pathway, defined as any process that modulates the frequency, rate or extent of IGF receptor signaling.
What genes are involved in regulation of insulin-like growth factor receptor signaling pathway?
Key genes include IGF1, IGF2, IGF1R, IGF2R, INSR, IRS1, IRS2, SHC1, PIK3CA, AKT1, MTOR, PTEN, and IGFBP family members.
How is IGF receptor signaling regulated?
It is regulated at the level of ligand bioavailability by IGFBPs, receptor expression and trafficking, phosphatase-mediated dephosphorylation, and downstream feedback through mTOR and SOCS proteins.
What diseases are linked to IGF receptor signaling?
Dysregulation is linked to hepatocellular carcinoma, non-small cell lung cancer, Alzheimer's disease, chronic migraine, and metabolic disorders.
What is the role of IGF1R in cancer?
IGF1R is a receptor tyrosine kinase that drives proliferation and survival; its hyperactivation contributes to tumor growth in several cancers.
How do researchers study GO:0043567?
Common methods include phospho-proteomics, RNA-seq, live-cell imaging of tagged receptors, functional proliferation assays, and CRISPR screens.
What is the difference between IGF1R and insulin receptor signaling?
Both receptors share IRS-PI3K-AKT downstream signaling and can form hybrid receptors, but they respond to different ligands and have distinct metabolic roles.
Can CRISPR knockout be used to study IGF receptor signaling?
Yes, CRISPR knockout of IGF1R, IGF1, IGF2, IRS1, or IRS2 is widely used to test the requirement of each component for pathway output.
What are IGFBPs and why do they matter?
IGFBPs are binding proteins that sequester IGF ligands and modulate their availability to IGF1R, making them key regulators of GO:0043567.
Is IGF receptor signaling a therapeutic target?
Yes, IGF1R and its ligands are being explored as therapeutic targets in oncology and neurology, though context-dependent effects require careful validation.
Conclusion
GO:0043567, regulation of insulin-like growth factor receptor signaling pathway, is a central biological process that integrates ligand availability, receptor activation, adaptor recruitment, and negative feedback to control growth, survival, and metabolism. Its dysregulation is implicated in cancer, neurodegeneration, and metabolic disease, making it a high-value area for mechanistic and translational research. CRISPR-based knockout, point mutation, knock-in, overexpression, and library screening approaches provide the causal toolkit needed to dissect this pathway and identify new therapeutic opportunities.
References
- 1. Choi E et al.. 2025. Regulation and function of insulin and insulin-like growth factor receptor signalling.. Nat Rev Mol Cell Biol 26(7):558-580 PMID: 39930003
- 2. Dilawar M et al.. 2026. Insulin-like growth factor receptor signaling in physiology and disease.. Signal Transduct Target Ther 11(1) PMID: 42722676
- 3. Breuhahn K et al.. 2008. Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma.. World J Gastroenterol 14(11):1690-8 PMID: 18350600
- 4. Wood AW et al.. 2005. Insulin-like growth factor signaling in fish.. Int Rev Cytol 243:215-85 PMID: 15797461
- 5. Miao J et al.. 2025. Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies.. Mol Neurobiol 62(3):3195-3225 PMID: 39240280
- 6. Wang T et al.. 2024. Targeting IGF1/IGF1r signaling relieve pain and autophagic dysfunction in NTG-induced chronic migraine model of mice.. J Headache Pain 25(1):156 PMID: 39304806
- 7. Ho S et al.. 2025. Insulin- Like Growth Factor-1 as Brain-Body Connector.. Adv Exp Med Biol 1477:83-104 PMID: 40442384
- 8. Xu X et al.. 2022. Different Roles of the Insulin-like Growth Factor (IGF) Axis in Non-small Cell Lung Cancer.. Curr Pharm Des 28(25):2052-2064 PMID: 36062855
