Insulin Signaling and RTK: An Overview

Explore the intricate world of Insulin Signaling and Receptor Tyrosine Kinases (RTKs), pivotal in regulating metabolism and influencing diseases like cancer and atherosclerosis.

The insulin signalling pathway is a series of steps that occur when insulin binds to its receptor on the surface of a cell. This results in the activation of various proteins, which then initiate a range of metabolic processes.

The insulin signalling pathway can be divided into three main stages:

The insulin receptor is a heterotetrameric complex of two α-subunits and two β-subunits that are disulfide linked. The insulin molecule binds to the extracellular α-subunits, which activate the intracellular tyrosine kinase domain of the β-subunit.

Insulin is a peptide hormone produced by the beta-cells of the pancreas that regulates human metabolism. Insulin binds to its receptor, causing a triphosphorylation of the activation loop. The kinase then phosphorylates tyrosine amino acids outside the kinase domain of the receptor, creating binding sites for signaling protein partners with SH2 (src-homology 2) domains or PTB (phosphotyrosine-binding) domains. The insulin receptors interact with the phosphorylated juxtamembrane domain residue of large docking proteins called IRS (Insulin receptor substrate) and the adapter Sh2 (Src homology 2 domain containing). The protein binds to and activates other proteins, such as SHC (src homology domain containing) and Grb-14 (growth factor receptor bound), which are part of the receptor complex. Following this, two pathways are activated: the Ras/MAP kinase pathway and the PI-kinase pathway.

The insulin receptor is a tyrosine kinase receptor (RTK) that is activated by the insulin hormone. The insulin RTK pathway regulates cellular responses to insulin, such as glucose uptake, membrane potential, protein tyrosine phosphorylation and glycolysis. The first step in the pathway is activated by binding of insulin to the insulin receptor. The second step is initiated with tyrosine kinase activity, which phosphorylates serine and threonine residues on proteins and initiates a cascade of intracellular events. This cascade then leads to gene expression, protein synthesis and cell growth.

The structure of RTKs consist of an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular region that includes a juxtamembrane regulatory area (TKD), as well as a tyrosine kinase domain (TKD) and a carboxyl terminal tail. RTK plays an important role in insulin signalling, which is the process by which insulin regulates the metabolism of glucose and other nutrients

There are four main types of RTKs: insulin receptor, IGF-I receptor (insulin-like growth factor I receptor), PDGF receptor (platelet derived growth factor receptor) and EGFR receptor (epidermal growth factor receptor). These receptors play an important role in regulating various aspects of cellular function, including proliferation, differentiation and survival. The insulin receptor is the most well studied RTK, and has been shown to play a role in cancer progression.

The Ras/MAP kinase pathway is activated by the insulin signaling pathway. The Ras/MAP kinase pathway is responsible for transmitting the signal from the receptor to the nucleus of the cell and the activation of a protein called Raf through the activity of Grb-14. Raf then activates two proteins called MEK and ERK, enter the nucleus and phosphorylate various transcription factors, which activate gene expression for genes that regulate metabolism. MEK, which in turn activates a protein called MAP kinase. The MAP kinase (MAPK) pathway plays an important role in regulating cell growth and survival.

The PI-kinase pathway is activated by the insulin signaling pathway. The PI-kinase pathway is responsible for the activation of a protein called PI-kinase and for relaying the signal from the receptor to the interior of the cell. This protein then phosphorylates other proteins, including PKB (protein kinase B) and PDK-I (phosphoinositide dependent kinase I),which regulates glucose metabolism. Phosphorylation of these proteins results in their activation, which leads to the regulation of various metabolism.

Once activated, PKB and PDK-I promote the fusion of GLUT-IV (glucose transporter type IV) with the cell membrane. GLUT-IV transports glucose into the cell, and GS (glucagon receptor), which regulates blood sugar levels. This allows glucose to enter the cell and be used for energy.

There are a number of proteins that act as negative regulators of insulin signalling. These proteins help to prevent the receptor from being activated too strongly and causing excessive cell proliferation. Some of the most well studied negative regulators of insulin signalling include PTEN (phosphatase and tensin homolog), FOXO (forkhead box O) and SREBP-lc (sterol regulatory element binding protein-lc).

PTEN is a lipid and protein tyrosine phosphatase that dephosphorylates the receptor, leading to its inactivation. PTEN is a tumor suppressor gene, and mutations in this gene are associated with various types of cancer.

FOXO is a transcription factor that regulates the expression of genes involved in metabolism and cell growth. FOXO has been shown to inhibit insulin signalling by blocking the activation of PKB.

SREBP-lc is a transcription factor that regulates the synthesis of cholesterol and other lipids. SREBP-lc has been shown to promote insulin resistance by inhibiting PKB activity.

Atherosclerosis is a complex pathological process that involves a variety of cells, including vascular, immune, and metabolic cells. Insulin signaling via the insulin receptors plays an essential role in vascular cells and vessel dilation and relaxation.

Increasing evidence suggests that hyperinsulinemia is linked to the development of atherosclerosis in diabetes. This is supported by human studies showing that insulin infusion in healthy persons causes vasodilation and improves blood flow to the peripheral tissues. These effects are dampened in those with insulin resistance and type 2 diabetes.

The receptor tyrosine kinase inhibitors (RTKIs) sunitinib, lapatinib and gefitinib have all been shown to reduce lesion size and inhibit foam cell formation in mice models of atherosclerosis.

There is growing evidence that receptor tyrosine kinases play a role in the development of cancer. Evidence suggests that Insulin receptors are over-expressed in cancer cells, especially those of the breast cancer. Increased insulin receptor expression is associated with shorter survival in breast cancers. Insulin receptors are frequently over-expressed and highly phosphorylated in breast tumors generated by diabetic mice.

The receptor tyrosine kinase inhibitors (RTKIs) sunitinib, lapatinib and gefitinib have all been shown to reduce tumor size and inhibit cell proliferation in various types of cancer cells.