INSR - insulin receptor |Elisa - Clia - Antibody - Protein

Background

The insulin receptor (INSR) is a transmembrane protein essential for regulating glucose homeostasis, cellular growth, and metabolism. This receptor, which belongs to the receptor tyrosine kinase (RTK) family, is the primary signaling molecule for insulin, a hormone central to controlling blood sugar levels. By binding insulin, the INSR initiates a cascade of signaling pathways that drive glucose uptake, protein synthesis, lipid metabolism, and cell proliferation. Dysregulation of INSR signaling is implicated in various metabolic and endocrine diseases, most notably type 2 diabetes mellitus (T2DM), obesity, and insulin resistance-related disorders. The receptor’s role in modulating these critical physiological processes makes it a focus for therapeutic interventions and research in metabolic diseases.

Protein Structure

The INSR is a heterotetrameric protein comprising two extracellular α-subunits and two transmembrane β-subunits, which are synthesized as a single precursor polypeptide. These subunits are linked by disulfide bonds, resulting in a α2β2 configuration that facilitates both insulin binding and signal transduction.

α-Subunits (Extracellular):

• The α-subunits are entirely extracellular and form the insulin-binding domain of the receptor. This domain contains several highly conserved regions that interact directly with the insulin molecule. The α-subunits are essential for high-affinity insulin binding, which is a key step in initiating downstream signaling.
• Structurally, the α-subunits are composed of cysteine-rich domains and a leucine-rich repeat domain. The cysteine-rich regions contribute to the receptor’s conformation and stability, essential for effective ligand binding. These extracellular regions undergo post-translational modifications, including N-linked glycosylation, which are critical for the proper folding, stability, and functionality of the receptor.

β-Subunits (Transmembrane and Cytoplasmic):

• The β-subunits consist of three main segments: a short extracellular domain, a single transmembrane domain, and an intracellular domain with tyrosine kinase activity. This intracellular domain is crucial for downstream signal transduction.
• Upon insulin binding to the α-subunits, conformational changes occur, leading to autophosphorylation of the tyrosine residues in the intracellular domain of the β-subunits. This phosphorylation activates the tyrosine kinase activity of the receptor, which subsequently phosphorylates downstream signaling molecules.
• The intracellular β-subunit domain includes three primary regions:
• Kinase Domain: This domain contains the active site responsible for transferring phosphate groups to tyrosine residues on substrate proteins.
• Regulatory Domain: This domain is responsible for maintaining the receptor in an inactive state in the absence of insulin. Binding of insulin to the extracellular domain induces conformational changes that relieve inhibition and activate the receptor.
• Phosphotyrosine-Binding Domain: Phosphorylated tyrosine residues in this domain serve as docking sites for various adapter proteins, including insulin receptor substrates (IRS), which propagate downstream signaling pathways.

Classification and Subtypes

INSR has two primary isoforms: INSR-A and INSR-B, which are generated by alternative splicing and differ in their affinity for ligands and their signaling properties:

• INSR-A (Exon 11 Skipped): INSR-A is the shorter isoform and lacks the region encoded by exon 11. This isoform has a high affinity for insulin-like growth factors (IGF), in addition to insulin. It is widely expressed in fetal tissues, where it plays a role in growth and development, and in certain cancer cells, where it promotes proliferation and survival.
• INSR-B (Full-Length Isoform): INSR-B contains all the protein regions encoded by the gene, including exon 11. This isoform has high specificity for insulin and is predominantly expressed in metabolic tissues, such as liver, muscle, and adipose tissue. It is primarily involved in regulating glucose metabolism.

The presence of these isoforms allows the INSR to mediate distinct physiological functions depending on tissue context, developmental stage, and cellular environment.

Function and Biological Significance

The INSR’s primary function is to mediate the effects of insulin, which include:

Glucose Uptake and Metabolism:

• Upon insulin binding, INSR activates signaling cascades that lead to the translocation of GLUT4 (glucose transporter type 4) to the cell membrane, facilitating glucose uptake in tissues such as skeletal muscle and adipose tissue. This glucose transport is crucial for maintaining blood glucose levels within a narrow range.
• Additionally, insulin signaling via INSR promotes glycogen synthesis in the liver and muscle by activating glycogen synthase, while inhibiting glycogen breakdown. These processes help store glucose and prevent hyperglycemia.

Lipid Metabolism:

• INSR activation influences lipid metabolism by promoting lipogenesis and inhibiting lipolysis in adipose tissue. Insulin signaling increases the activity of enzymes responsible for synthesizing fatty acids and triglycerides, facilitating energy storage during periods of nutrient abundance.
• The receptor also inhibits lipolysis by downregulating hormone-sensitive lipase, reducing the release of free fatty acids into circulation.

Protein Synthesis and Cell Growth:

• Insulin signaling through INSR promotes protein synthesis by activating the mTOR pathway and enhancing the translation of mRNAs for various cellular proteins. This anabolic action is crucial for tissue repair, growth, and development.
• INSR signaling also contributes to cell proliferation and growth by modulating the PI3K/AKT and MAPK pathways. This function is particularly prominent in fetal tissues expressing INSR-A and certain tumors, where insulin signaling supports cell survival and growth.

Anti-Apoptotic Effects:

• INSR signaling has anti-apoptotic effects, particularly in insulin-sensitive tissues, by activating pathways that prevent programmed cell death. This is achieved through the PI3K/AKT pathway, which is important for maintaining tissue integrity and cellular function, especially in the liver and muscle.

Clinical Issues

Given its central role in metabolism, alterations in INSR function or expression are implicated in a variety of diseases:

Type 2 Diabetes Mellitus (T2DM):

• T2DM is characterized by insulin resistance, where target tissues like muscle and liver exhibit a decreased response to insulin despite its presence. This insulin resistance is often linked to post-receptor defects in INSR signaling, which impair glucose uptake and lead to hyperglycemia. Insulin resistance can stem from genetic mutations in the INSR gene, abnormal receptor expression, or downstream signaling defects.
• Managing T2DM often involves enhancing insulin sensitivity through lifestyle changes and pharmacological agents, with some drugs targeting INSR signaling to improve glucose control.

Insulin Resistance Syndromes:

• Severe insulin resistance can arise from mutations in the INSR gene, leading to syndromes such as Type A insulin resistance, Donohue syndrome, and Rabson-Mendenhall syndrome. These conditions are characterized by extreme hyperinsulinemia, glucose intolerance, and, in some cases, developmental abnormalities.
• Patients with these syndromes exhibit mutations that impair the receptor’s ability to bind insulin or transmit signals, severely impacting metabolic homeostasis and growth.

Cancer:

• Overexpression of INSR, particularly the INSR-A isoform, has been observed in various cancers, where it promotes tumorigenesis by enhancing cell survival, proliferation, and migration. INSR-A’s ability to bind IGFs, in addition to insulin, gives cancer cells an advantage in growth and survival.
• Targeting INSR or its pathways has been explored as a potential cancer therapy, particularly in tumors with high insulin receptor expression.

Obesity:

• Obesity is closely associated with insulin resistance, partly due to alterations in INSR signaling in adipose tissue. Chronic inflammation and lipotoxicity associated with obesity can disrupt INSR function, leading to systemic insulin resistance and metabolic dysregulation.

Summary

The insulin receptor (INSR) is a pivotal protein in regulating glucose and lipid metabolism, growth, and cellular survival. Structurally, INSR is a heterotetramer comprising extracellular α-subunits that bind insulin and intracellular β-subunits with tyrosine kinase activity that transduce signals. This receptor exists in two main isoforms, INSR-A and INSR-B, each adapted to different physiological roles: INSR-A is involved in growth and development, while INSR-B plays a critical role in glucose homeostasis.

INSR mediates its effects by activating various signaling pathways, notably the PI3K/AKT and MAPK pathways, which regulate glucose uptake, lipid synthesis, protein production, and cell survival. Dysregulation of INSR signaling is linked to metabolic diseases like T2DM, insulin resistance syndromes, and obesity, as well as certain cancers where INSR-A promotes tumorigenesis. The receptor's broad biological impact and role in disease make it a major therapeutic target, with ongoing research focused on modulating INSR signaling to treat metabolic and proliferative disorders.