IGF2R - insulin like growth factor 2 receptor|Elisa - Clia - Antibody - Protein

Background

The insulin-like growth factor 2 receptor (IGF2R) is a multi-functional transmembrane protein primarily known for binding and internalizing insulin-like growth factor 2 (IGF-2). Unlike the insulin-like growth factor 1 receptor (IGF1R), which signals to promote cell proliferation and survival, IGF2R generally acts to limit the bioavailability of IGF-2 and is therefore considered a negative regulator of growth. IGF2R also binds other ligands, including mannose-6-phosphate-tagged proteins, such as lysosomal enzymes, which it transports from the Golgi to lysosomes.

This receptor is widely expressed in mammalian tissues and has important roles in development, cellular signaling, and protein trafficking. IGF2R is unique in its signaling capacity, as it lacks intrinsic tyrosine kinase activity. It operates mainly through ligand sequestration, ligand degradation, and the modulation of signaling pathways indirectly by reducing IGF-2 interactions with IGF1R. IGF2R’s role in growth regulation and its involvement in diseases, particularly cancer, has made it a focal point in biomedical research.

Protein Structure

The IGF2R protein is a large, complex receptor encoded by the IGF2R gene and is classified as a type I transmembrane protein. Structurally, it comprises a long extracellular domain, a single transmembrane region, and a short cytoplasmic tail.

Extracellular Domain:

• The extracellular domain of IGF2R consists of 15 repeated domains termed extracellular or ligand-binding repeats. These repeats are critical for the receptor’s binding capacity. Domains 3, 5, and 9 are specifically responsible for binding to IGF-2, while other repeats contribute to binding mannose-6-phosphate (M6P)-tagged ligands.
• The M6P binding sites allow IGF2R to capture lysosomal enzymes in the Golgi and transport them to lysosomes, a critical function for cellular protein degradation and recycling.
• Structurally, each repeat is stabilized by disulfide bonds, and the receptor's flexibility allows it to bind multiple ligands.

Transmembrane Domain:

• The transmembrane domain is a single hydrophobic segment that anchors IGF2R in the cell membrane, providing structural stability while facilitating ligand internalization.

Cytoplasmic Tail:

• IGF2R has a relatively short cytoplasmic tail compared to other receptors. Although it lacks intrinsic kinase activity, it contains motifs that mediate interactions with adaptor proteins involved in endocytosis.
• The cytoplasmic tail plays a significant role in the internalization of the receptor-ligand complex, directing IGF2R-bound ligands to the endosomal-lysosomal system for degradation or trafficking back to the cell surface.

Classification and Subtypes

IGF2R is a member of the mannose-6-phosphate receptor (M6PR) family, sharing functional similarities with the cation-independent mannose-6-phosphate receptor (CI-MPR), which is similarly involved in lysosomal enzyme trafficking. However, there are no functional subtypes of IGF2R; it exists in a single form across various tissue types.

Hybrid complexes between IGF2R and other receptors are not typical, given that IGF2R does not share significant structural overlap with IGF1R or INSR, which primarily engage in cell signaling. Instead, IGF2R functions independently to sequester and degrade IGF-2 and transport M6P-modified proteins.

Function and Biological Significance

IGF2R has several essential biological functions, primarily in growth regulation, protein trafficking, and cellular signaling. Its functions can be summarized as follows:

IGF-2 Sequestration and Regulation of Cell Growth:

• IGF2R’s binding and sequestration of IGF-2 limit the interaction of IGF-2 with IGF1R, a receptor that promotes cell growth and proliferation. By controlling IGF-2 availability, IGF2R indirectly suppresses IGF1R signaling, acting as a tumor-suppressive mechanism.
• This regulatory function is critical during development, where IGF2R helps maintain appropriate growth rates and organ development by limiting IGF-2’s proliferative effects.

Lysosomal Enzyme Transport:

• IGF2R binds mannose-6-phosphate-tagged proteins in the Golgi and facilitates their transport to lysosomes. This function is crucial for maintaining lysosomal function, as lysosomes depend on a constant supply of enzymes to degrade cellular waste and recycle biomolecules.
• In this pathway, IGF2R binds M6P-modified enzymes, transports them to endosomes, and then releases them in acidic lysosomal compartments.

Receptor-Mediated Endocytosis and Ligand Degradation:

• IGF2R is a key player in receptor-mediated endocytosis, a process by which cells internalize extracellular molecules. Once IGF2R binds IGF-2 or M6P-modified ligands, the receptor-ligand complex is internalized and transported to endosomes. IGF2R releases its ligands in the low-pH environment of the endosome, allowing IGF-2 to be degraded or, in the case of lysosomal enzymes, to be transported to lysosomes.
• This endocytic mechanism ensures that IGF-2 does not freely circulate in excess, thus preventing excessive cell proliferation and maintaining cellular homeostasis.

Tumor Suppressor Role:

• IGF2R is frequently described as a tumor suppressor, as it prevents excessive IGF-2-driven proliferation. Loss of IGF2R function or mutations in the IGF2R gene that reduce IGF-2 binding have been associated with cancers, where unchecked IGF-2 availability drives malignant growth.
• Through its IGF-2 degradation pathway, IGF2R modulates the growth environment, creating a suppressive impact on oncogenesis by reducing IGF-2 stimulation of growth-promoting receptors.

Clinical Issues

Mutations, loss of expression, or altered function of IGF2R have significant clinical implications, especially in cancer, growth disorders, and metabolic diseases:

Cancer:

• IGF2R’s role as a tumor suppressor means that reduced IGF2R expression or mutations that impact its ligand-binding ability can contribute to tumorigenesis. In cancers such as breast, liver, and lung cancer, reduced IGF2R function has been observed, leading to increased IGF-2 activity and enhanced cell proliferation.
• IGF2R gene mutations or allelic loss are implicated in the progression of various cancers, making IGF2R a potential target for therapeutic intervention.

Beckwith-Wiedemann Syndrome (BWS):

• BWS is a genetic overgrowth syndrome linked to IGF2 and IGF2R dysregulation. In this syndrome, loss of IGF2R function or epigenetic alterations in the IGF2 gene can lead to excessive IGF-2 signaling, causing overgrowth, an increased risk of embryonal tumors, and other developmental anomalies.
• Genetic or epigenetic changes affecting the IGF2R locus are common in BWS, underscoring the receptor’s role in growth regulation and development.

Growth Disorders:

• Alterations in IGF2R function can lead to growth abnormalities due to disruptions in IGF-2 signaling. While rare, IGF2R mutations or dysregulation can be associated with dwarfism or gigantism, depending on whether IGF-2 activity is suppressed or enhanced.

Cardiovascular and Metabolic Disorders:

• Dysregulation of IGF2R has been suggested to contribute to cardiovascular diseases, as IGF signaling impacts endothelial cell proliferation, vascular integrity, and metabolic processes. Altered IGF2R expression may affect these pathways, linking it indirectly to cardiovascular health.

Summary

The insulin-like growth factor 2 receptor (IGF2R) is a unique multifunctional receptor that plays essential roles in growth regulation, lysosomal enzyme trafficking, and endocytosis. IGF2R is a type I transmembrane protein with a large extracellular domain composed of 15 ligand-binding repeats, a single transmembrane domain, and a short cytoplasmic tail. It functions mainly by binding IGF-2 and mannose-6-phosphate-tagged proteins, sequestering IGF-2 to reduce its bioavailability and transporting lysosomal enzymes to the lysosomes. This function is critical for growth regulation and maintaining cellular homeostasis.

IGF2R’s role as a growth regulator makes it a key tumor suppressor. Its ability to sequester IGF-2 prevents excessive IGF-2 signaling through IGF1R, thereby inhibiting uncontrolled cell proliferation. Clinically, IGF2R mutations or reduced function are associated with various cancers, where increased IGF-2 activity promotes malignancy. Additionally, IGF2R dysregulation is implicated in genetic syndromes like Beckwith-Wiedemann Syndrome, which involves overgrowth due to excessive IGF-2 activity.

Overall, IGF2R is a vital receptor in cellular biology, with significant roles in development, cancer biology, and lysosomal function. Its unique structure and functions make it a promising target for understanding and treating diseases associated with IGF-2 dysregulation.