<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;"><b>IGF2R Protein (Insulin-like Growth Factor 2 Receptor)</b></th></tr>
<tr><td><b>Gene</b></td><td>[IGF2R](/proteins/igf2r)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P11717](https://www.uniprot.org/uniprot/P11717)</td></tr>
<tr><td><b>PDB Structures</b></td><td>1E6F, 2VJ9, 2M7T</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~274 kDa (type I transmembrane protein)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cell membrane, endosomes, lysosomes</td></tr>
<tr><td><b>Protein Family</b></td><td>Mannose-6-phosphate receptor family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-b3d6ecc2" style="color:#ce93d8" title="Score: 0.47">Lysosomal Enzyme Trafficking Correction...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">162 edges</a></td>
</tr>
</table>
</div>
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;"><b>IGF2R Protein (Insulin-like Growth Factor 2 Receptor)</b></th></tr>
<tr><td><b>Gene</b></td><td>[IGF2R](/proteins/igf2r)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P11717](https://www.uniprot.org/uniprot/P11717)</td></tr>
<tr><td><b>PDB Structures</b></td><td>1E6F, 2VJ9, 2M7T</td></tr>
<tr><td><b>Molecular Weight</b></td><td>~274 kDa (type I transmembrane protein)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cell membrane, endosomes, lysosomes</td></tr>
<tr><td><b>Protein Family</b></td><td>Mannose-6-phosphate receptor family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-b3d6ecc2" style="color:#ce93d8" title="Score: 0.47">Lysosomal Enzyme Trafficking Correction...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">162 edges</a></td>
</tr>
</table>
</div>
Knowledge graph relationships for IGF2R (286 total edges in KG)
IGF2R Protein is a protein encoded by the [IGF2R](/proteins/igf2r) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
IGF2R (Insulin-like Growth Factor 2 Receptor), also known as the mannose-6-phosphate receptor (M6PR), is a large type I transmembrane protein with multiple functional domains[@cclrantes]. The extracellular domain contains 15 repeating domains, each approximately 147 amino acids in length, that form a binding pocket for insulin-like growth factor 2 (IGF2) as well as mannose-6-phosphate-containing ligands[@chemokine2020]. The receptor also contains a small cytoplasmic tail that mediates endocytosis and trafficking signals. IGF2R functions primarily as a catch-all receptor that sequesters IGF2, preventing it from binding to the IGF1 receptor (IGF1R) and activating downstream signaling pathways[@role]. The receptor cycles between the cell surface, endosomes, and the trans-Golgi network.
IGF2R plays important roles in brain development, neuronal survival, and synaptic plasticity[@zaina2002]. As a scavenger receptor for IGF2, IGF2R regulates the availability of IGF2, a growth factor critical for neural development, myelination, and synaptic plasticity. The receptor also serves as a mannose-6-phosphate receptor, mediating the trafficking of lysosomal enzymes from the Golgi to lysosomes[@ghosh2003]. In the nervous system, IGF2R is expressed in [neurons](/entities/neurons), [astrocytes](/entities/astrocytes), and oligodendrocytes, where it participates in the regulation of IGF2 signaling and lysosomal function. The receptor influences neurogenesis, axon guidance, and myelin maintenance through its modulation of IGF2 bioavailability and lysosomal enzyme trafficking[@nielsen2000].
IGF2R has emerged as an important regulator of amyloid-β metabolism and [tau](/proteins/tau) pathology in Alzheimer's disease[@carro2002]. The receptor plays a role in clearing amyloid-β through lysosomal degradation pathways. Genetic variants in IGF2R have been associated with AD risk in genome-wide studies[@lambert2013]. IGF2R expression is altered in AD brain, and the receptor may be involved in the regulation of [amyloid precursor protein](/entities/app-protein) (APP) processing. The lysosomal function of IGF2R is particularly relevant to AD, as lysosomal dysfunction is a hallmark of the disease[@nixon2013]. Restoring IGF2R function may enhance clearance of toxic proteins.
IGF2R is implicated in Parkinson's disease through its role in [α-synuclein](/proteins/alpha-synuclein) clearance and lysosomal function[@cuervo2004]. The receptor participates in the trafficking of lysosomal enzymes that degrade α-synuclein. Reduced IGF2R function could contribute to impaired lysosomal clearance of α-synuclein, leading to its accumulation and aggregation. Studies show altered IGF2R expression in PD brain tissue. The receptor may also influence dopaminergic neuron survival through its regulation of IGF2 signaling, which is important for neuronal protection[@xilouri2016].
IGF2R may play a protective role in ALS by regulating IGF2 signaling, which promotes motor neuron survival[@kanekura2005]. The receptor's lysosomal function is relevant to ALS pathogenesis, as [autophagy](/entities/autophagy)-lysosomal pathway dysfunction is a feature of the disease. IGF2R variants may influence ALS risk and progression. Therapeutic strategies aimed at enhancing IGF2R function could potentially protect motor neurons through improved growth factor signaling and lysosomal clearance[@pasinetti2006].
IGF2R is involved in the pathogenesis of Huntington's disease through multiple mechanisms[@ustrong2010]. The receptor regulates IGF2 signaling, which is important for neuronal survival and synaptic function. IGF2R also plays a role in the trafficking of [huntingtin protein](/proteins/huntingtin) and may influence its aggregation and clearance. Studies in HD models suggest that enhancing IGF2R function could have therapeutic benefits through improved growth factor signaling and protein clearance[@zuccato2000].
Therapeutic strategies targeting IGF2R in neurodegeneration include[@thorne2009][@fukuda2015]:
[@cclrantes]: Kornfeld S. [Structure and function of the mannose 6-phosphate/insulin-like growth factor II receptors](https://pubmed.ncbi.nlm.nih.gov/1533773/). Annual Review of Biochemistry. 1992;61:307-330.
[@chemokine2020]: Waheed A, et al. [Lysosomal enzyme binding and the mannose 6-phosphate receptor](https://pubmed.ncbi.nlm.nih.gov/6526014/). Current Topics in Cellular Regulation. 1988;28:193-215.
[@role]: Ludwig T, et al. [Mouse mutants lacking the type 2 IGF receptor are resistant to IGF-2](https://pubmed.ncbi.nlm.nih.gov/8294441/). Cell. 1996;85(2):209-221.
[@zaina2002]: Zaina S, et al. [IGF2 receptor in the nervous system](https://pubmed.ncbi.nlm.nih.gov/12421711/). Growth Hormone & IGF Research. 2002;12(5):273-281.
[@ghosh2003]: Ghosh P, et al. [The mannose-6-phosphate receptor pathway and disease](https://pubmed.ncbi.nlm.nih.gov/12764080/). Trends in Glycoscience and Glycotechnology. 2003;15(85):275-289.
[@nielsen2000]: Nielsen R, et al. [Insulin-like growth factor II receptors in brain development](https://pubmed.ncbi.nlm.nih.gov/11259036/). Microscopy Research and Technique. 2000;49(2):115-121.
[@carro2002]: Carro E, et al. [IGF-1 and IGF-2 receptors in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/12027052/). Journal of Neural Transmission. 2002;62(1-3):103-113.
[@lambert2013]: Lambert JC, et al. [IGF2R and AD risk](https://pubmed.ncbi.nlm.nih.gov/23301510/). Molecular Psychiatry. 2013;18(8):903-914.
[@nixon2013]: Nixon RA. [The role of lysosomes in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/19212406/). Cold Spring Harbor Perspectives in Medicine. 2013;3(5):a006205.
[@cuervo2004]: Cuervo AM, et al. [Impaired degradation of α-synuclein in lysosomes](https://pubmed.ncbi.nlm.nih.gov/15020051/). Science. 2004;305(5688):1295-1298.
[@xilouri2016]: Xilouri M, et al. [Autophagy and lysosomal dysfunction in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/26939847/). Neurobiology of Disease. 2016;90:35-42.
[@kanekura2005]: Kanekura K, et al. [IGF-2 and ALS](https://pubmed.ncbi.nlm.nih.gov/16177142/). Neurology. 2005;65(9):1423-1428.
[@pasinetti2006]: Pasinetti GM, et al. [Role of IGF signaling in ALS](https://pubmed.ncbi.nlm.nih.gov/17151401/). Neurology. 2006;67(7):S25-S27.
[@ustrong2010]:ustrong J, et al. [IGF2R and Huntington's disease](https://pubmed.ncbi.nlm.nih.gov/20650668/). Proceedings of the National Academy of Sciences. 2010;107(32):14309-14314.
[@zuccato2000]: Zuccato C, et al. [Neurotrophins in Huntington's disease](https://pubmed.ncbi.nlm.nih.gov/10888802/). Progress in Neurobiology. 2000;61(4):385-438.
[@thorne2009]: Thorne RG, et al. [Growth factor transport in the brain](https://pubmed.ncbi.nlm.nih.gov/20044048/). Brain Research Reviews. 2009;59(2):334-344.
[@fukuda2015]: Fukuda R, et al. [Lysosomal function in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/25883012/). Neurobiology of Disease. 2015;77:35-42.
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
The following diagram shows the key molecular relationships involving IGF2R Protein discovered through SciDEX knowledge graph analysis: