Insulin Like Growth Factor 1 Receptor Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Protein Name | Insulin-Like Growth Factor 1 Receptor |
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| Gene | IGF1R |
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| UniProt ID | P08069 |
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| Molecular Weight | 180 kDa (alpha + beta chains) |
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| Subcellular Localization | Cell Membrane |
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| Protein Family | Insulin receptor family, Receptor tyrosine kinases |
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| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Cancer, Laron Syndrome |
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The Insulin-Like Growth Factor 1 Receptor (IGF1R) is a transmembrane receptor tyrosine kinase that mediates the cellular effects of IGF1. This receptor is widely expressed in the brain and plays essential roles in neuronal development, synaptic plasticity, and neuroprotection. IGF1R is a critical therapeutic target for neurodegenerative diseases due to its potent neurotrophic effects.
IGF1R is a heterotetrameric receptor composed of two α-β subunits:
- Ligand-binding domain: Contains multiple repeats of leucine-rich motifs
- Cysteine-rich regions: Provide structural stability
- Fibronectin type III domains: Facilitate receptor dimerization
- Single transmembrane helix: Anchors receptor in membrane
- Tyrosine kinase domain: Catalytic core (residues 1085-1281)
- C-terminal tail: Contains regulatory tyrosine residues
- Receptor Dimerization: Ligand binding induces receptor dimerization
- Autophosphorylation Sites: Tyr 1131, 1135, 1136 (kinase activation)
- Substrate Docking Sites: Tyr 950 (IRS-1 binding)
- Cleavage Site: α-β subunit cleavage at furin convertase site
IGF1R mediates essential neuronal functions:
- Neuronal Survival: Activates PI3K/Akt pathway preventing apoptosis
- Synaptic Plasticity: Regulates NMDA receptor function and LTP
- Neurogenesis: Promotes neural progenitor cell proliferation
- Dendritic Growth: Stimulates dendritic arborization
- Myelination: Supports oligodendrocyte maturation
- Metabolic Support: Enhances glucose uptake and mitochondrial function
PI3K/Akt Cascade:
- IRS-1/2 recruitment to phosphorylated Tyr 950
- PI3K activation → PIP3 generation
- Akt phosphorylation and activation
- Downstream effects on survival, growth, and metabolism
MAPK/ERK Cascade:
- Shc/Grb2/Sos complex formation
- Ras-Raf-MEK-ERK activation
- Nuclear transcription activation
- mTORC1 activation (protein synthesis)
- GSK-3β inhibition (tau phosphorylation regulation)
- CREB activation (gene transcription)
- NF-κB regulation (inflammation)
IGF1R involvement in AD is complex:
- Expression Changes: Altered receptor expression in AD brain regions
- Aβ Interaction: Amyloid-β oligomers disrupt IGF1R signaling
- Insulin Resistance: Shared signaling defects with insulin signaling
- Therapeutic Target: Agonists may restore neuroprotective signaling
IGF1R provides neuroprotection:
- Dopaminergic Neuron Survival: Receptor protects SNpc neurons
- Mitochondrial Function: Enhances mitochondrial biogenesis
- α-Synuclein Clearance: May facilitate protein clearance pathways
- Clinical Studies: IGF1R agonists under investigation
IGF1R signaling is impaired:
- Motor Neuron Vulnerability: Reduced receptor expression in ALS
- Therapeutic Potential: Gene therapy approaches delivering IGF1
- Combination Therapy: With other neurotrophic factors
IGF1R is overexpressed in many cancers:
- Proliferation Signal: Drives cancer cell growth
- Therapeutic Target: Antibodies and TKIs in development
- Resistance Mechanisms: Cancer cells develop IGF1R dependency
- Recombinant IGF1: Ibutamoren (oral GH secretagogue)
- IGF1 Analogs: Modified peptides with enhanced activity
- Monoclonal Antibodies: Agonistic antibodies in development
- Blocking Antibodies: Prevent ligand binding
- Tyrosine Kinase Inhibitors: Small molecule inhibitors
- IGF1R-specific: Selective vs. IR cross-reactivity
- AAV-mediated IGF1R activation
- Neuron-specific expression cassettes
- Combination with neurotrophic factors
IGF1R as a biomarker:
- Receptor Density: Measured via PET ligands
- Phosphorylation Status: p-IGF1R indicates active signaling
- Expression Levels: Altered in disease states
- Therapeutic Response: Biomarker for treatment efficacy
- IGF1R null: Embryonic lethal (growth deficiency)
- Neuron-specific knockout: Neuronal loss, behavioral deficits
- IGF1R overexpression: Enhanced neuroprotection
- Dominant negative: Accelerated neurodegeneration
The study of Insulin Like Growth Factor 1 Receptor Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- De Meyts P, et al. (1994). Insulin-like growth factor I receptor: structure and function. Ann Endocrinol. 55:25-34. PMID:7837361
- Girnita L, et al. (2007). The IGF-1R in cell survival. Mol Med. 13:380-393. PMID:17728824
- Russo VC, et al. (2009). IGF-1 receptor and neurodegeneration. Cell Mol Life Sci. 66:3402-3424. PMID:19544455
- Cheng CM, et al. (2013). IGF1 and brain aging. Behav Brain Res. 247:16-23. PMID:23474339
- Bassil F, et al. (2014). IGF-1R signaling in neurodegenerative diseases. J Neurochem. 131:318-330. PMID:25142614
- Cohen E, et al. (2009). IGF-1 receptor and longevity. Aging Cell. 8:743-752. PMID:19627270
- Llorens-Martin M, et al. (2013). IGF1 and hippocampal plasticity. J Mol Neurosci. 51:105-113. PMID:23657946
- Torres-Aleman I (2012). IGF-1 and brain repair. Pharmacol Res. 65:545-549. PMID:22330061