IGF1R - insulin like growth factor 1 receptor |Elisa - Clia - Antibody - Protein

Background

The insulin-like growth factor 1 receptor (IGF1R) is a transmembrane receptor that plays a crucial role in cellular growth, survival, and metabolism. It is activated primarily by insulin-like growth factor 1 (IGF-1), a hormone structurally similar to insulin but with distinct biological functions. IGF1R is a member of the receptor tyrosine kinase (RTK) family, which includes receptors like the insulin receptor (INSR). IGF1R signaling is essential for normal development and is involved in many physiological processes, such as cell differentiation, proliferation, and apoptosis inhibition. This receptor is also significant in pathological states, especially cancer, where it can drive tumor growth and metastasis through enhanced cell survival and proliferation pathways.

Protein Structure

IGF1R is a heterotetrameric receptor composed of two extracellular α-subunits and two transmembrane β-subunits. The subunits are linked by disulfide bonds, forming an α2β2 configuration essential for ligand binding and signal transduction.

α-Subunits (Extracellular):

• The α-subunits are located entirely outside the cell and form the IGF-1 binding domain. These subunits are responsible for the high-affinity binding of IGF-1 and, to a lesser degree, IGF-2. Structurally, the α-subunits contain cysteine-rich regions and a leucine-rich repeat domain that contribute to the receptor’s binding properties.
• The α-subunits undergo N-linked glycosylation, a post-translational modification that ensures proper folding, stability, and function. Glycosylation is critical for the receptor's structural integrity and affinity for its ligands.

β-Subunits (Transmembrane and Cytoplasmic):

• Each β-subunit has a short extracellular region, a single transmembrane domain, and a cytoplasmic region that contains the tyrosine kinase domain. The transmembrane segment anchors the receptor to the cell membrane, allowing extracellular IGF-1 binding to influence intracellular signaling.
• The intracellular portion of the β-subunits contains tyrosine residues that undergo autophosphorylation when IGF-1 binds to the receptor. This phosphorylation activates the tyrosine kinase activity of IGF1R, initiating downstream signaling.
• The β-subunit contains three primary domains:
• Kinase Domain: The kinase domain is responsible for transferring phosphate groups to tyrosine residues on substrate proteins, a key step in signal transduction.
• Regulatory Domain: This region helps maintain the receptor in an inactive state until ligand binding triggers activation.
• Phosphotyrosine-Binding Sites: Phosphorylated tyrosine residues in this domain serve as docking sites for adapter proteins, such as insulin receptor substrate (IRS) and SH2-domain containing proteins, which propagate signaling pathways.

Classification and Subtypes

The IGF1R shares structural similarity with the insulin receptor (INSR), and the two receptors can form hybrid receptors that respond to both IGF-1 and insulin. However, there are no primary subtypes of IGF1R itself, as it primarily exists in a single form across tissues.

Hybrid receptors formed between IGF1R and INSR can respond to both insulin and IGFs, though with varying affinities depending on the composition. For example, IGF1R-INSR hybrids have higher affinity for IGF-1 and are mainly found in tissues where both receptors are co-expressed, such as muscle and adipose tissue.

Function and Biological Significance

IGF1R plays a central role in several fundamental biological processes by mediating the effects of IGF-1, including:

Cell Growth and Proliferation:

• IGF1R activation stimulates cellular growth and proliferation by triggering the PI3K/AKT and MAPK signaling pathways. These pathways are critical for cell cycle progression and are frequently activated in cells requiring rapid growth or repair.
• The receptor’s activation promotes DNA synthesis and protein production, processes essential for normal development and tissue regeneration.

Survival and Anti-Apoptotic Effects:

• IGF1R has potent anti-apoptotic properties. Activation of the receptor prevents programmed cell death by signaling through the PI3K/AKT pathway, which in turn inhibits pro-apoptotic proteins and promotes cell survival.
• This anti-apoptotic function is particularly important in embryonic development and tissue maintenance, where cell survival is critical. In pathologies like cancer, this survival signaling can be exploited by tumor cells to evade apoptosis.

Metabolic Regulation:

• While not as prominent as the insulin receptor in glucose homeostasis, IGF1R does play a role in metabolism, particularly in tissues where it is co-expressed with INSR. Activation of IGF1R influences glucose and lipid metabolism, enhancing nutrient utilization and energy storage.
• In muscle tissue, IGF1R promotes glucose uptake and protein synthesis, supporting anabolic processes that are critical for muscle growth and repair.

Developmental Processes:

• IGF1R is essential for proper growth and development. Mice lacking functional IGF1R exhibit severe growth defects and die shortly after birth, highlighting its crucial role in fetal development.
• In humans, mutations in IGF1R can lead to growth deficiencies, as the receptor is integral to processes like bone growth, cell differentiation, and organogenesis.

Clinical Issues

Due to its involvement in growth and survival signaling, alterations in IGF1R function or expression are associated with various diseases, particularly cancers and growth disorders.

Cancer:

• IGF1R is overexpressed in numerous cancers, including breast, prostate, and lung cancers. The receptor's role in promoting cell proliferation and inhibiting apoptosis makes it a key driver of tumorigenesis and cancer progression.
• Cancer cells often exploit IGF1R signaling to evade cell death, support uncontrolled growth, and facilitate metastasis. This has made IGF1R a significant target for cancer therapy, with several inhibitors and monoclonal antibodies developed to disrupt IGF1R signaling. However, clinical success has been limited due to challenges such as receptor redundancy and pathway resistance.

Insulin Resistance and Metabolic Disorders:

• In conditions such as obesity and type 2 diabetes, IGF1R signaling may be dysregulated, particularly in tissues that co-express INSR. This dysregulation can contribute to insulin resistance, as IGF1R signaling overlaps with and can interfere with insulin signaling pathways.
• IGF1R signaling also affects lipid metabolism, and dysregulation in adipose tissue can exacerbate metabolic imbalances seen in metabolic syndrome.

Growth Disorders:

• Mutations in IGF1R can lead to growth deficiencies, such as IGF1R haploinsufficiency, where reduced receptor function results in poor postnatal growth and development. Individuals with IGF1R mutations often exhibit short stature, delayed bone age, and sometimes cognitive impairments.
• Genetic testing for IGF1R mutations can help diagnose these growth disorders and guide treatment, such as growth hormone therapy, to support normal development.

Aging and Longevity:

• IGF1R signaling has been implicated in aging, with studies suggesting that reduced IGF1R activity may be linked to increased lifespan. Lower IGF1R activity decreases cellular proliferation and metabolic rates, which may reduce oxidative stress and DNA damage accumulation.
• Research in model organisms indicates that modulation of IGF1R signaling could influence aging processes, though translating these findings to human longevity requires further investigation.

Summary

The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase crucial for growth, survival, and metabolic regulation. Structurally, IGF1R is a heterotetramer with two extracellular α-subunits and two transmembrane β-subunits. The α-subunits form the IGF-1 binding domain, while the β-subunits contain a tyrosine kinase domain that transduces signals upon ligand binding. This structure enables IGF1R to respond to IGF-1 and initiate downstream signaling pathways, including PI3K/AKT and MAPK, which drive cell growth, proliferation, and survival.

Functionally, IGF1R is essential for normal development, influencing processes such as bone growth, muscle regeneration, and metabolic regulation. It has potent anti-apoptotic effects, supporting cell survival in various tissues. However, dysregulation of IGF1R signaling is associated with diseases, particularly cancers, where IGF1R promotes tumor growth and resistance to apoptosis. IGF1R is also linked to metabolic and growth disorders, underscoring its role in human health.

Given its extensive role in both physiology and pathology, IGF1R is a major target for therapeutic intervention. Efforts to inhibit IGF1R in cancer have shown promise, though challenges remain due to pathway redundancy and resistance mechanisms. Overall, IGF1R remains a crucial receptor in cellular biology and a significant focus for research into growth regulation, cancer therapy, and aging.