What is Insulin?
- Insulin is a naturally occurring peptide hormone produced by the pancreas, specifically by beta cells in the islets of Langerhans.
- It’s a protein hormone composed of two chains (A and B) linked by disulfide bonds.
- First successfully isolated and used in 1921 by Frederick Banting and Charles Best, revolutionizing diabetes treatment.
How Insulin receptor mediated signaling works?
Phase 1: The Master Switch (Initiation)
Ligand Binding: Insulin (or IGF-1/2) binds to the extracellular alpha subunits of the insulin receptor (IR).
Conformational Change: Binding triggers a shape change across the membrane, activating the tyrosine kinase (Tyr-K) domains on the intracellular beta subunits.
Autophosphorylation: The receptor performs trans-autophosphorylation, where the two beta subunits phosphorylate each other to create docking sites for signaling proteins.
Phase 2: The Docking Station (Substrate Recruitment)
The activated IR recruits several primary substrates, which act as a hub for the signal to split into two distinct directions:
1. IRS (Insulin Receptor Substrates): The primary mediators for metabolic signals family of signaling proteins specifically phosphorylating IRS-1 and IRS-2
2. SHC: A protein that primarily initiates the growth-related signaling cascade.
Pathway 2: The Mitogenic Pathway
(Ras/MAPK/ERK)
Function: Responsible for cell proliferation,
survival, and differentiation.
Activates insulin
receptor upon insulin binding activates SHC by phosphorylation
1. Adaptor Assembly: Phosphorylated SHC (or
IRS) recruits the GRB2-SOS complex.
2. Ras Activation: SOS triggers Ras
to exchange GDP for GTP, switching Ras to its "on" position.
3. The Kinase Cascade: Activated Ras triggers a
sequence of phosphorylation: Raf --> MEK -> ERK1/2.
4. Nuclear Entry: Activated ERK (MAPK)
moves into the nucleus.
5. Growth Actions:
Gene Expression: Regulates transcription factors
like c-Myc and c-Fos.
Promotes expression of genes
involved in cell division and growth where as inhibiting genes of apoptosis
Metabolic Actions triggered by
this pathway
Cell Cycle: Promotes cell division,
migration, and inhibits programmed cell death (apoptosis).