Lecture 4: Receptor Tyrosine Kinases and Insulin Signaling

Module 8: Topic 4 – Receptor Tyrosine Kinases

Introduction

  • Discussing receptor tyrosine kinases, focusing on the insulin receptor as a second class.
  • Relation of insulin receptor to diabetes and its importance in glucose regulation.

Insulin Receptor Overview

  • Function of Insulin Receptor: Controls glucose uptake in the bloodstream.
    • Normal Range of Glucose: Approximately 5 millimolar necessary in the blood for various cellular functions.
    • Diabetes: Type 1 and Type 2 diabetes are characterized by ineffective insulin signaling leading to glucose accumulation in the blood, which is harmful.

Insulin Receptor Structure

  • Dimer Formation: Insulin receptor forms a dimeric structure (two units).
    • Hormone Binding Sensitivity: Requires only one insulin molecule to bind to one of the receptors, effectively turning off hormone binding to the other dimer, enhancing signaling sensitivity.
  • Receptor Composition: Alpha and Beta Chains
    • Structure: Composed of an alpha2 beta2 complex with disulfide bonds (similar to antibodies).
    • **Extracellular Domains:
    • L1 Domain:** Leucine-rich domain.
    • Cysteine-rich Domain:
    • Second L1 Domain: Another leucine-rich domain.
    • Cytoplasmic Domain: Contains multiple tyrosine residues that require phosphorylation for function.

Signaling Pathway of Insulin Receptor

  • Tyrosine Phosphorylation: Phosphorylated tyrosines act as docking sites for adapter proteins.
  • **Activation Mechanism:
    • Phosphorylation Process:** Insulin binds to the receptor, activates the receptor through phosphorylation, which is facilitated by ATP.

Pathways Regulated by Insulin

  • Two primary pathways following activation:
    • **Glucose Regulation Pathway:
    • Insulin Receptor Substrate (IRS-1):** Key player in directing the signaling towards glucose regulation.
    • **Growth Regulation Pathway:
    • SHC Protein:** Directs signaling towards growth processes, particularly in development.
Specific Interactions
  • IRS Protein (IRS-1): Targets glucose pathways.
  • SHC Protein: Targets growth regulation pathways.
  • Binding Mechanism: Requires specific nearby components in the receptor for effective interaction (e.g., phosphotyrosine binding domains).

Key Proteins in the Signaling Pathway

  • SH2 Domain: Present in both IRS-1 and SHC proteins, facilitates binding to phosphotyrosines.
    • SH2 Domain of GRAB2 Protein: An intermediary that connects signaling processes but does not directly interact with the insulin receptor.
  • **Binding Specificity:
    • IRS-1:** Recognizes phosphotyrosines adjacent to alanine.
    • SHC:** Binds to phosphotyrosines adjacent to specific amino acids like glutamate.

PI3-kinase Activation and Function

  • PI3-Kinase: Major player following IRS-1 recruitment.
    • Structure: Composed of p85 (regulatory) and p110 (catalytic) subunits.
  • Conversion Process:
    • Converts PIP2 (phosphatidylinositol 4,5-bisphosphate) to PIP3 (phosphatidylinositol 3,4,5-trisphosphate).
    • Mechanism: PIP3 formation involves phosphorylation of the 3-position on the sugar, highlighting its importance for signaling.
    • Activates downstream phosphoproteins including AKT.

Downstream Effects of PIP3

  • Role of PIP3: Acts as a docking site for proteins like PDK1 and AKT, facilitating their recruitment and subsequent signaling events.
    • PDK1 Function: Phosphorylates AKT, activating it for downstream signaling involved in glucose metabolism.
  • Insulin Signaling Outcomes: Multiple steps lead to effective glucose regulation and other downstream biological effects.

Summary of Signaling Mechanisms

  • Ensure understanding of each step sequentially, especially how insulin signaling leads to glucose regulation and the importance of protein interactions in signaling pathways.
  • Implications for diabetes and metabolic regulation highlighted, alongside the mechanisms that ensure precise physiological response to insulin.

Conclusion

  • Emphasize the complexity and interconnectedness of these pathways, illustrating the importance of these receptors in health and disease management, specifically regarding diabetes and metabolic syndrome.