insulin receptor signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals generated as a consequence of the insulin receptor binding to insulin. [GOC:ceb]

The insulin receptor signaling pathway is a complex cascade of events that begins with the binding of insulin to its receptor on the cell surface. This binding triggers a series of intracellular signaling events that ultimately lead to the regulation of glucose metabolism, protein synthesis, and cell growth. Here is a detailed description of the key steps involved:

1. **Insulin Binding and Receptor Dimerization:** Insulin binds to its receptor, a transmembrane protein composed of two alpha and two beta subunits. The binding of insulin causes the two alpha subunits to come together, bringing the two beta subunits closer as well. This dimerization activates the receptor's tyrosine kinase activity.

2. **Autophosphorylation of the Insulin Receptor:** The activated tyrosine kinase domain of the receptor phosphorylates itself on several tyrosine residues within the beta subunit. This autophosphorylation creates binding sites for other signaling proteins.

3. **Recruitment of Insulin Receptor Substrate (IRS):** Phosphorylated tyrosine residues on the receptor serve as docking sites for the Insulin Receptor Substrate (IRS) proteins. IRS proteins are adaptor proteins that relay the signal downstream.

4. **IRS Phosphorylation:** Once bound to the receptor, IRS proteins are phosphorylated on multiple tyrosine residues by the activated receptor kinase. This phosphorylation creates binding sites for other signaling proteins, such as phosphatidylinositol 3-kinase (PI3K).

5. **Activation of PI3K and Akt:** PI3K binds to phosphorylated IRS proteins and is activated. Activated PI3K phosphorylates phosphatidylinositol (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 serves as a docking site for Akt, a serine/threonine kinase. Akt is then phosphorylated and activated by two other kinases, PDK1 and mTORC2.

6. **Akt-mediated Signaling:** Activated Akt plays a central role in the insulin signaling pathway. It phosphorylates and regulates a variety of downstream targets involved in glucose metabolism, protein synthesis, and cell growth. These targets include:
* **GLUT4 Translocation:** Akt promotes the translocation of glucose transporter 4 (GLUT4) from intracellular vesicles to the plasma membrane. This increases glucose uptake by cells.
* **Glycogen Synthase Kinase 3 (GSK3) Inhibition:** Akt inhibits GSK3, which in turn activates glycogen synthase, leading to increased glycogen synthesis and glucose storage.
* **mTOR Activation:** Akt activates mTOR, a key regulator of protein synthesis and cell growth.
* **FOXO Transcription Factors Inhibition:** Akt phosphorylates and inhibits FOXO transcription factors, which regulate genes involved in gluconeogenesis (glucose production).

7. **Negative Regulation:** The insulin signaling pathway is tightly regulated to prevent excessive signaling and maintain homeostasis. Several mechanisms contribute to this regulation, including:
* **Protein Tyrosine Phosphatases (PTPs):** PTPs dephosphorylate the insulin receptor and IRS proteins, terminating the signaling cascade.
* **Insulin Receptor Substrate (IRS) Degradation:** IRS proteins are degraded by the ubiquitin-proteasome system, limiting the duration of insulin signaling.
* **Phosphatase and Tensin Homolog (PTEN):** PTEN dephosphorylates PIP3, reducing the activity of Akt.

The insulin receptor signaling pathway is essential for normal glucose metabolism and is dysregulated in various metabolic diseases, such as type 2 diabetes. Understanding the intricate details of this pathway is crucial for developing novel therapies for these diseases.

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Proteins (32)

Compounds (796)