Design
01
Define Perturbation and Construct
Choose knockout, knockdown, or variant introduction based on the hypothesis, and confirm the transcript version and cell background before design.
Gene Function, Pathways, and Disease Evidence
IGF2R and Associated Diseases
IGF2R encodes the cation-independent mannose-6-phosphate receptor, a multifunctional type I transmembrane protein that binds IGF2 at the cell surface and mannose-6-phosphate-tagged proteins in the secretory pathway. Its established receptor functions provide a basis for testing disease associations, but mechanistic conclusions require function-specific readouts, appropriate perturbation models, and rescue or independent validation.
IGF2R connects IGF2 clearance with mannose-6-phosphate-dependent lysosomal enzyme trafficking. Human tumor studies and mouse knockout-and-rescue experiments provide different levels of evidence for its disease relevance, making it essential to distinguish genetic association from a demonstrated mechanism. A practical study should begin by identifying which receptor function could explain the phenotype, then select a model and pathway-specific readouts to test that hypothesis. Engineered cell models and siRNA screening offer complementary ways to examine receptor dependence. Mechanistic conclusions should rest on concordant functional measurements and rescue or independent validation, with interpretation limited to the model and perturbation tested.
Receptor identityOne receptor, two ligand classes: IGF2 at the surface, mannose-6-phosphate-tagged proteins in the secretory pathway.
Trafficking axisReceptor cycling between trans-Golgi network, plasma membrane, and endosomes determines both ligand delivery and clearance.
Evidence levelLoss of heterozygosity, reduced expression, and pathway-level links are different evidence types with different limits.
Stable Identifiers and Scope
What entity is being discussed?
Entity identifiers prevent the most common project error: designing against the wrong transcript or the wrong receptor family member. Confirm the versioned record before construct design.
01Approved symbol and full nameIGF2R; insulin-like growth factor 2 receptor. The protein is commonly referred to as M6P/IGF2R, CI-MPR, or CD222.
02Locus and familyHuman locus 6q25.3. It belongs to the mannose-6-phosphate receptor family and is distinct from the cation-dependent receptor (M6PR), which has a separate set of experimental considerations.
03Protein architectureType I single-pass transmembrane protein of roughly 300 kDa, with a large extracellular region of repeated domains, a single transmembrane segment, and a short cytoplasmic tail bearing sorting motifs.
04Authoritative database recordsNCBI Gene ID 3482; HGNC ID 5467; UniProt P11717 (MPRI_HUMAN); OMIM 147280. Verify the versioned transcript and assembly before design. Last verified October 20, 2026.
05Imprinting contextThe mouse orthologue is subject to genomic imprinting with parent-of-origin expression differences. Human imprinting of the locus is not established in the same way, so imprinting assumptions should not be carried across species without checking.
06Scope of this pageReceptor biology, reported disease associations, and validation approaches. It does not provide diagnostic or therapeutic recommendations.
Two Ligand Classes, One Receptor
What does the receptor actually do?
Normal receptor function is well characterized at the cell-biological level. Which of these functions explains a disease association is the part that usually remains a hypothesis.
01Mannose-6-phosphate-dependent enzyme traffickingIn the trans-Golgi network the receptor binds newly synthesized lysosomal hydrolases bearing mannose-6-phosphate tags and carries them toward endosomes, where the acidic environment releases the cargo. This is the canonical, best-supported function.
02IGF2 clearance at the cell surfaceAt the plasma membrane the receptor binds IGF2 and routes it for degradation, lowering available IGF2. This links the receptor to growth signaling, and is the function most often invoked when receptor loss is discussed in a tumor context.
03Activation of latent TGF-betaBinding of latency-associated peptide or related ligands to the receptor has been reported to contribute to activation of latent TGF-beta. This places the receptor in a fibrogenic and immunomodulatory signaling context.
04Endocytic and recycling itineraryThe cytoplasmic tail contains sorting signals that govern internalization and recycling. Assays that measure only total receptor level can miss a trafficking defect, which is a recurring reason for contradictory results.
05Apoptosis and cell-fate contextThe receptor has been linked to apoptotic pathways and to innate immune functions in published work. The mechanistic direction depends on cell type and on which ligand axis dominates in that system.
06Normal versus disease-state expressionExpression is broad but not uniform. Reduced expression in a tumor sample may reflect loss of the locus, transcriptional regulation, or the composition of the sampled tissue; these are different explanations requiring different assays.
Association Type Determines the Claim
Which disease associations are reported, and how strong are they?
Each association below rests on a different evidence type. Loss of heterozygosity, reduced expression, and pathway-level involvement are not equivalent, and none of them establishes causality on its own.
| Context | Evidence type | What supports it | Limit and interpretation boundary |
|---|---|---|---|
| Hepatocellular carcinoma | Loss of heterozygosity and mutation reports at 6q25-ter | Studies from the mid-1990s reported frequent LOH at the M6P/IGF2R locus in human hepatocellular tumors, with mutations described in tumors showing LOH | A candidate tumor-suppressor framing is a hypothesis supported by genetic evidence, not a demonstrated causal requirement. LOH frequency varies between studies and cohorts. |
| Non-small cell lung cancer | Reduced expression associated with stage, treatment response, and outcome | Expression analyses and cell-line knockdown work, where reduced receptor level was associated with increased proliferation, migration, and invasion phenotypes | Expression level is a correlate. Direction of causation, and whether the effect runs through IGF2 clearance or M6P trafficking, is not settled by expression data alone. |
| Squamous cell carcinoma of the lung | Mutation reports in tumor tissue | Published work described receptor mutations in squamous cell tumors | Reported mutation frequencies vary by cohort and detection method; confirm against current curated datasets before citing a rate. |
| Mucolipidosis II alpha/beta | Pathway-level relationship, not a primary causal locus | The disease results from defective N-acetylglucosamine-1-phosphotransferase, which impairs mannose-6-phosphate tagging. The receptor is the downstream reader of that tag | The receptor is part of the affected pathway, not the gene primarily responsible. Association should be stated as pathway-level. |
| Growth and perinatal lethality models | Engineered mouse models | Receptor-null mice show overgrowth and perinatal lethality that can be rescued on IGF2- or IGF1R-null backgrounds, connecting the receptor to IGF2 clearance in vivo | Mouse imprinting and dosing differ from the human situation; the rescue result is specific to the tested genetic backgrounds. |
| Fibrosis and TGF-beta-linked phenotypes | Mechanistic hypothesis | Receptor-dependent activation of latent TGF-beta has been reported in cell systems | Hypothesis-level in most disease contexts. Requires ligand-specific and receptor-specific evidence, not inference from total receptor level. |
01Hepatocellular Carcinoma: Candidate Tumor Suppressor
LOH+
Mechanism and Research Findings
- The locus resides in a region long suspected to contain a liver tumor suppressor. Loss of heterozygosity at 6q25-ter was reported in a substantial fraction of hepatocellular tumors, and mutations were described in tumors that showed LOH.
- Two mechanistic readings are usually proposed: reduced IGF2 clearance increasing growth signaling, or altered lysosomal enzyme routing affecting cell behavior.
Evidence and Interpretation
- Evidence: human tumor genetic analyses with supporting functional work.
- Interpretation: consistent with a candidate tumor-suppressor role at that locus.
- Limit: reported frequencies vary; a locus-level finding does not identify the causal gene within the region on its own.
02Non-Small Cell Lung Cancer: Expression and Phenotype
Expression+
Mechanism and Research Findings
- Lower receptor expression has been associated with higher tumor stage, reduced treatment responsiveness, and poorer outcome in reported analyses.
- In cell-line work, knockdown increased proliferation, migration, and invasive behavior and altered apoptosis readouts, providing a functional counterpart to the expression correlation.
Evidence and Interpretation
- Evidence: expression datasets plus in vitro perturbation.
- Interpretation: supports a functional role in cell behavior in the tested lines.
- Limit: correlation plus knockdown does not establish causality in patients, and the responsible ligand axis is not resolved by either result.
03Mucolipidosis II: Pathway-Level, Not Causal
Pathway+
Mechanism and Research Findings
- Mucolipidosis II alpha/beta is caused by defective tagging of lysosomal enzymes with mannose-6-phosphate. The receptor is the reader of that tag.
- This makes the receptor part of the affected pathway rather than the primary causal gene.
Evidence and Interpretation
- Evidence: biochemical and genetic characterization of the tagging pathway.
- Interpretation: receptor function is required for the pathway to operate normally.
- Limit: describing the receptor as causal for the disease would be incorrect; state the relationship as pathway-level.
04IGF2 Axis and Growth Control
Signaling+
Mechanism and Research Findings
- Receptor-null mice show overgrowth and perinatal lethality, and the phenotype is rescued when IGF2 or IGF1R is also absent. This is direct genetic evidence that the receptor normally limits IGF2 availability.
- The result is the clearest mechanistic anchor for the growth-control narrative.
Evidence and Interpretation
- Evidence: engineered mouse models with genetic epistasis.
- Interpretation: establishes the IGF2-clearance function in vivo.
- Limit: mouse imprinting and gene dosage differ from human; the rescue is specific to the tested backgrounds.
05TGF-beta Activation and Fibrosis Hypotheses
Hypothesis+
Mechanism and Research Findings
- Cell-based work reported that binding of latent TGF-beta complexes to the cation-independent mannose-6-phosphate receptor can participate in activation of the latent cytokine.
- This is often used to connect the receptor to fibrogenic and immunomodulatory phenotypes.
Evidence and Interpretation
- Evidence: cell-based biochemical studies.
- Interpretation: plausible mechanism in systems where the receptor and latent complex are both present.
- Limit: hypothesis-level in most disease contexts; requires direct measurement of active TGF-beta rather than inference.
06Conflicting Reports and Reporting Boundaries
Boundary+
Mechanism and Research Findings
- Both tumor-suppressive and tumor-promoting readings appear in the literature, often because different assays measure different functions or different compartments.
- Antibody specificity, transcript versus protein measurement, and tissue composition each explain part of the disagreement.
Evidence and Interpretation
- Evidence: heterogeneous across studies.
- Interpretation: state which function and compartment was measured before comparing reports.
- Limit: an association should not be restated as causation in project documentation.
Choosing a System That Can Refute the Hypothesis
Which models and readouts test an IGF2R hypothesis?
The table below connects the question to a model and a readout. Methods listed as screening, confirmation, or orthogonal serve different roles; not every item is required for every project.
| Question | Recommended approach | Controls | Primary readout | Role and limit |
|---|---|---|---|---|
| Is the receptor required for the phenotype in this cell type? | Gene knockout or knockdown in the relevant line | Non-targeting control, independent clones, parental line | Viability, proliferation, migration, invasion | Screening. Clone effects require independent clones; knockdown is not equivalent to null. |
| Is trafficking or clearance affected? | Ligand uptake and cathepsin secretion assays | Receptor-null or knockdown line, rescue construct | Secreted versus intracellular lysosomal enzyme ratio, IGF2 uptake | Confirmation. Distinguishes a trafficking defect from a level change. |
| Which ligand axis explains the effect? | Ligand-specific perturbation: IGF2 supplementation or blockade, TGF-beta reporter | Ligand-only and receptor-only conditions | Downstream pathway reporters, active TGF-beta | Orthogonal. Active ligand must be measured, not assumed. |
| Can expression be restored to test rescue? | Re-expression with a construct resistant to the perturbation; vector design and construction should account for cassette size and the target cell | Empty vector, wild-type construct, and a trafficking-deficient mutant where relevant | Restoration of the readout toward control range | Confirmation. Failure to rescue may indicate an off-target or clone-specific effect. |
| Does the association hold in a more physiological system? | Primary cells, iPSC-derived cells, or disease modeling with gene editing | Isogenic control line | Panel matching the cell-line readouts plus expression confirmation | Orthogonal. Isogenic comparison is required, otherwise background differences confound the result. |
| Is a variant functionally different? | Variant-specific editing donor design or construct comparison | Wild-type construct, benign-variant construct where available | Trafficking, ligand binding, and downstream readouts | Confirmation. A variant without a functional difference is not evidence against association. |
From Construct to Interpretable Conclusion
How is a gene-function study organized?
Each step has an entry condition and an output. Skipping the rescue step is the most common reason a gene-function claim cannot be defended.
Validation
02
Confirm Expression and Localization
Confirm the intended change and check surface versus intracellular distribution. A level change without a localization check cannot distinguish a trafficking defect.
Phenotype
03
Measure Functional Phenotype
Run the assay panel defined during design, including ligand-axis-specific measurements where the hypothesis depends on IGF2 or TGF-beta.
Specificity
04
Perform Rescue and Orthogonal Checks
Re-expression should move the readout toward control. A second, method-independent measurement helps separate a real effect from an assay artifact.
Interpretation
05
Interpret Within the System
Report the model, controls, replication, and observation window. State the result as an association or a mechanism only at the level the data support.
Correlation is not mechanism
A difference in receptor level between conditions is an association. A mechanism requires a perturbation, a specific readout, and a rescue or orthogonal test that could have failed.
Unresolved Scientific Questions
What still limits consistent interpretation?
The receptor has two ligand classes and several reported associations. That combination produces apparently contradictory results when studies measure different functions, compartments, or species.
-
Two functions, one measurement.
A change in IGF2 clearance and a change in lysosomal enzyme routing are distinct outcomes. A single total-protein measurement cannot distinguish them, which is a frequent source of conflicting conclusions.
-
Correlation versus causality.
LOH and reduced expression are associations. Establishing that the receptor drives a phenotype requires perturbation and rescue in a defined system, with the result reported at that level.
-
Species and imprinting differences.
Mouse models show imprinted expression and a strong growth phenotype with genetic rescue. Human imprinting at the locus is not established in the same way, so cross-species extrapolation needs explicit justification.
-
Antibody and assay specificity.
Receptor quantification depends on antibody validation and on whether transcript, total protein, or surface protein is measured. Discrepancies between these measures are expected and should be reported rather than averaged away.
-
Tissue composition.
Bulk tissue expression reflects cell-type composition. Without a composition control or single-cell resolution, an apparent expression change may reflect sampling rather than regulation.
-
Material and construct quality.
Editing efficiency, construct integrity, and vector characterization affect every downstream readout. Compare only preparations characterized with the same panel; see viral vector analysis.
Published Experimental Evidence
Research Progress in IGF2R Studies
Two examples illustrate different evidence types: human tumor genetic analysis, and engineered mouse models with genetic rescue. Each supports a different kind of claim.
01
Human Tumor Genetic Evidence
LOH and Mutation at the M6P/IGF2R Locus in Liver Tumors
De Souza and colleagues reported frequent loss of heterozygosity on chromosome 6q at the mannose-6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors, and described mutations in tumors showing LOH. The finding established the locus as a candidate tumor-suppressor region. It is genetic evidence for a candidate role and does not, by itself, demonstrate which gene in the region drives the phenotype.
See references
02
Engineered Mouse Model Evidence
Receptor Loss, Overgrowth, and Genetic Rescue
Mice lacking the type 2 IGF receptor show overgrowth and perinatal lethality. Ludwig and colleagues reported that this lethality is rescued on IGF2-null and IGF1R-null backgrounds, placing the receptor within the IGF2 clearance axis in vivo. Wang and colleagues reported related growth and lysosomal targeting phenotypes. These results support a specific mechanism in mouse and require separate justification in human systems.
See references
Build Evidence Around the Receptor Function
Creative Biolabs Support
Creative Biolabs supports IGF2R studies through gene perturbation, engineered cell models, expression constructs, and research vector production. Start with the receptor function you intend to test: IGF2 clearance, lysosomal enzyme trafficking, or a defined downstream phenotype. Provide the transcript, cell background, perturbation, and readout so the project can be scoped around a testable hypothesis.
01 / LOSS OF FUNCTION
Test receptor dependence
Define the cell background and target region for IGF2R loss-of-function work. Plan independent clones and parental controls, and measure receptor expression alongside the phenotype.
Scope and outputs to agree: An agreed knockout strategy, genotype verification, and clone documentation. Functional assays are specified separately.
02 / KNOCKDOWN SCREENING
Compare partial receptor suppression
Use sequence-based suppression to examine effects of reduced receptor abundance before committing to a clonal model. Compare independent siRNAs and non-targeting controls with receptor-level and viability measurements.
Scope and outputs to agree: Candidate sequences, a defined screening panel, and results for the agreed knockdown and cellular endpoints.
03 / VARIANT MODELS
Introduce a defined genetic change
Share the variant, reference sequence, cell line, and intended comparison. Discuss a CRISPR-assisted model that separates the introduced change from background differences.
Scope and outputs to agree: An editing and clone-selection plan, sequence verification, and an agreed isogenic comparison strategy.
04 / PRECISE EDITING
Prepare donor constructs
Define the desired sequence change or tag and the validation needed to preserve interpretation of receptor localization and function. Tag placement and donor design should follow the biological question.
Scope and outputs to agree: Donor construct design, annotated sequence records, and verification requirements for the intended edit.
05 / RESCUE EXPERIMENTS
Restore expression with a suitable vector
Specify full-length or domain-specific IGF2R, target cells, and the intended expression level. Review cassette size and delivery compatibility before selecting a vector; include empty-vector and expression-matched controls.
Scope and outputs to agree: An agreed expression construct and research material scope, with sequence records and characterization appropriate to the selected platform.
Project inputs, model compatibility, controls, and analytical methods determine the final scope. Specialized functional assays and animal procedures should be specified during technical review.
Primary Literature and Authoritative Sources
References
Gene identity
NCBI. IGF2R; Gene ID 3482. HGNC:5467. UniProtKB:P11717. OMIM:147280. Human gene and protein records. Accessed October 20, 2026. https://www.ncbi.nlm.nih.gov/gene/3482
Receptor biology · 2003
Ghosh P, Dahms NM, Kornfeld S. Mannose 6-phosphate receptors: new twists in the tale. Nature Reviews Molecular Cell Biology. 2003;4:202–213. https://doi.org/10.1038/nrm1050
Structure and function · 1992
Kornfeld S. Structure and function of the mannose 6-phosphate receptors. Annual Review of Biochemistry. 1992;61:307–330. https://doi.org/10.1146/annurev.bi.61.070192.001515
Lysosomal sorting · 2009
Braulke T, Bonifacino JS. Sorting of lysosomal proteins. Biochimica et Biophysica Acta. 2009;1793:605–614. https://doi.org/10.1016/j.bbamcr.2008.10.016
TGF-beta activation · 1991
Dennis PA, Rifkin DB. Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose-6-phosphate/insulin-like growth factor type II receptor. Proceedings of the National Academy of Sciences USA. 1991;88:580–584. https://doi.org/10.1073/pnas.88.2.580
Liver tumors · 1995
De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nature Genetics. 1995;11:447–449. https://doi.org/10.1038/ng1295-447
Lung squamous tumors · 2000
Kong FM, Anscher MS, Washington MK, Killian JK, Jirtle RL. M6P/IGF2R is mutated in squamous cell cancer of the lung. Oncogene. 2000;19:1572–1578. https://doi.org/10.1038/sj.onc.1203425
Mouse model · 1994
Wang ZQ, Fung MR, Barlow DP, Wagner EF. Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature. 1994;372:464–467. https://doi.org/10.1038/372464a0
Genetic rescue · 1996
Ludwig T, Eggenschwiler J, Fisher P, D'Ercole AJ, Davenport ML, Efstratiadis A. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Developmental Biology. 1996;177:517–535. https://doi.org/10.1006/dbio.1996.0182
Central nervous system review
Hawkes C, Kar S. The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Research Reviews. 2004;44:117–140. https://doi.org/10.1016/j.brainresrev.2003.11.002
Receptor signaling review
El-Shewy HM, Luttrell LM. Insulin-like growth factor-2/mannose-6 phosphate receptors. Vitamins and Hormones. 2009;80:667–697. https://doi.org/10.1016/S0083-6729(08)00624-9
Pathway boundary
Mucolipidosis II alpha/beta is caused by variants in the N-acetylglucosamine-1-phosphotransferase subunits rather than in IGF2R; IGF2R participates in the affected mannose-6-phosphate pathway. See the curated records at OMIM 252500 and NCBI Gene 3482.
Scientific Questions
Questions About IGF2R Research
Direct answers about receptor function, disease associations, models, and interpretation of gene-function results.
It binds mannose-6-phosphate-tagged lysosomal enzymes in the secretory pathway and routes them toward lysosomes, and it binds IGF2 at the cell surface and clears it. One receptor, two ligand classes, two measurable functions.
It is described as a candidate tumor suppressor in hepatocellular carcinoma, supported by loss of heterozygosity and mutation reports. That is genetic evidence for a candidate role, not proof of a causal requirement, and reports differ between cohorts.
Studies measure different things: transcript, total protein, or surface protein; IGF2 clearance or enzyme trafficking; bulk tissue or defined cells. State which compartment and function was measured before comparing results.
An isogenic or parental control plus independent clones, and a rescue experiment in which receptor expression is restored. Without rescue, an observed phenotype cannot be attributed specifically to receptor loss.
No. Mucolipidosis II alpha/beta results from defective mannose-6-phosphate tagging by the phosphotransferase complex. The receptor reads that tag and is part of the affected pathway, so the relationship should be stated as pathway-level.
The hypothesis and primary readout, versioned transcript and any variant in HGVS format, the intended perturbation, cell background and material status, control plan, and target timeline. Confidentiality needs can be raised at first contact.
Not directly. The mouse locus is imprinted, and receptor-null mice show a strong growth phenotype rescued on IGF2-null backgrounds. Human imprinting is not established the same way, so extrapolate with stated justification.
No. It is intended for research planning. It is not diagnostic or therapeutic advice and does not replace clinical evaluation by a qualified healthcare professional.
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