IGF1R

The IGF1R gene encodes the insulin-like growth factor 1 receptor, a critical cell surface receptor that regulates growth, development, metabolism, and survival by activating key intracellular signaling pathways. 

Disruptions in IGF1R activity are linked to a range of clinical manifestations including growth disorders, cancer progression, and vascular diseases.

What is IGF1R?

The IGF1R gene on chromosome 15q26.3 encodes the insulin-like growth factor 1 receptor (IGF1R), a cell surface receptor with intrinsic tyrosine kinase activity. IGF1R is activated when it binds to insulin-like growth factor 1 (IGF-1), a hormone structurally similar to insulin. 

Once activated, IGF1R regulates several critical biological processes, including cell growth and division, survival against programmed cell death (apoptosis), metabolism, and prenatal and postnatal development. Its role is essential for normal growth and tissue maintenance.

IGF1R Signaling Pathways

When IGF-1 binds to IGF1R, the receptor undergoes autophosphorylation on key tyrosine residues, such as Tyr-1161, Tyr-1165, and Tyr-1166. 

This autophosphorylation event activates multiple intracellular signaling pathways: 

• The PI3K-AKT-mTOR pathway promotes protein synthesis and cell survival, helping cells avoid apoptosis. 
• The RAS-MAPK pathway drives cell growth and division. 
• IGF1R also activates the JAK-STAT pathway, particularly STAT3, which promotes transcription of genes supporting growth and survival. 

Additionally, IGF1R can inhibit JNK-mediated pro-apoptotic signals by phosphorylating and inactivating MAP3K5, further protecting cells from death.

IGF1R Structure and Function

IGF1R is a tetramer composed of two extracellular α-subunits, responsible for ligand binding, and two intracellular β-subunits that contain the tyrosine kinase domain. 

Beyond its homodimeric form, IGF1R can form hybrid receptors with the insulin receptor (INSR), modifying its binding affinities and signaling specificity. 

This structural flexibility enables IGF1R to participate in a wide range of biological responses depending on the cellular environment.

Clinical Implications

Altered IGF1R activity may interfere with growth hormone suppression and have the following clinical implications:

Growth Disorders

Mutations affecting IGF1R function can lead to growth abnormalities. Loss-of-function mutations can cause IGF-1 resistance, resulting in conditions such as intrauterine growth restriction (IUGR), postnatal short stature, microcephaly, and elevated serum IGF-1 levels despite poor growth. 

Genetic testing and functional assays of IGF1R may help diagnose these unexplained growth delays.

Cancer

Overactive IGF1R signaling is implicated in tumor progression and resistance to standard therapies. Many cancers, including breast, prostate, and hematologic malignancies, show high IGF1R expression. 

IGF1R-targeted therapies are being developed to inhibit its role in tumor growth and survival. 

Vascular Health

IGF1R plays important roles in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), promoting proliferation, migration, nitric oxide production, and angiogenesis. 

Reduced IGF1R signaling in the vasculature contributes to atherosclerosis, restenosis after vascular injury, diabetic vascular disease, and hypertension. 

Loss of IGF1R activity in blood vessels can increase vascular fragility and plaque instability, suggesting its importance for maintaining vascular health.

When is IGF1R Testing Relevant?

IGF1R testing is primarily used in research or specialized clinical settings. It is frequently studied in the context of growth disorders, cancers, and metabolic diseases. 

IGF1R has been investigated for growth disorders in conditions such as IGF-1 resistance, short stature, and acromegaly. 

In cancer, IGF1R signaling is often dysregulated, promoting tumor growth, survival, and metastasis, which makes it a promising therapeutic target. 

In metabolic disease research, alterations in the IGF1R pathway may be associated with type 2 diabetes and insulin resistance. 

However, routine IGF1R testing is not performed in the general clinical setting and remains largely investigational or reserved for select oncology cases.

Functional IGF1R Testing Procedure

Functional testing of IGF1R evaluates the amount of functional IGF1R protein present on the surface of patient cells and how well it responds to IGF-I stimulation. 

The main method used is fluorescence-activated cell sorting (FACS), which measures IGF1R levels on live fibroblasts or peripheral blood mononuclear cells (PBMCs) after staining with a fluorescently labeled anti-IGF1R antibody. 

A reduction of about 50% in surface IGF1R compared to controls suggests haploinsufficiency. 

To assess IGF1R signaling function, Western blotting is performed on fibroblasts after IGF-I stimulation to measure phosphorylation of key signaling proteins like AKT. Together, FACS and Western blotting provide a functional profile of IGF1R availability and activity.

IGF1R Genetic Testing: Test Procedure and Interpretation

Testing for IGF1R is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for IGF1R genetic testing are considered to be without mutations that can alter the activity of the IGF1R proteins.

What Do Altered IGF1R Levels or Function Mean?

Altered IGF1R activity may have clinical implications in the following settings:

Growth Disorders

Decreased IGF1R activity can cause significant growth problems including IUGR, postnatal short stature, and microcephaly, often accompanied by elevated circulating IGF-1 levels that reflect poor receptor function. 

Conversely, increased IGF1R activity has been associated with overgrowth syndromes.

Cancer

In cancer, IGF1R is frequently overexpressed, helping tumors grow, resist cell death, and spread to other tissues. 

Its role as a survival signal has led to the development of experimental therapies targeting IGF1R, including monoclonal antibodies and tyrosine kinase inhibitors designed to block its activity.

Metabolic Disease

Dysregulated IGF1R signaling may contribute to metabolic abnormalities such as impaired glucose metabolism and insulin resistance. Abnormal activity of IGF1R can disrupt glucose handling and metabolic homeostasis, potentially increasing the risk of diabetes-related complications.

What Does the Absence of IGF1R Variants Mean?

The absence of known IGF1R mutations does not exclude the possibility of growth, cancer, or metabolic disorders. Many other genetic and environmental factors influence these complex processes. 

Therefore, IGF1R testing results must be interpreted carefully and in the context of a patient's overall clinical presentation, laboratory results, and family history.

Key Clinical Takeaways

IGF1R is critical for normal growth, tissue development, metabolic regulation, and tumor biology. Alterations in IGF1R function can cause significant clinical conditions, from growth failure and short stature to aggressive cancers. 

Testing for IGF1R function, such as assessing phosphorylation status or expression levels, can be useful in diagnosing certain growth disorders and predicting cancer therapy responses. 

Ongoing research continues to explore IGF1R as a promising therapeutic target in oncology and other fields.

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