Biochemistry Online: An Approach Based on Chemical Logic

Biochemistry Online





Learning Goals/Objectives for Chapter 9C:
After class and this reading, students will be able to

  • define kinases and phosphatases and their role in signal transduction
  • define primary and secondary messengers and give specific examples of each
  • describe the role of G proteins in coupling ligand induced conformational changes in the bound receptor to activation of specific effector proteins such as adenylate cyclase and phospholipase
  • differentiate between kinases activated by second messengers and those activated by primary messengers (ligand-gated receptor Tyr kinases)
  • describe the structural characteristics of G protein coupled serpentine receptors and ligand gated receptor tyrosine kinases
  • draw a diagram showing the general features of kinases mediated signal transduction pathways that lead to activation of gene expression
  • differentiate between neuron responses mediated by neurotransmitters on binding gated receptor/ion channels compares to G-protein coupled receptors

Estonian Translation by Anna Galovich

C9.  Insulin Signaling - PI3K and Akt (Protein Kinase B)

Type 2 diabetes, in which people become resistant to insulin which leads to high blood sugar and the cascade of health consequences that follow, is pandemic in the world.  Hence a brief look at two of the kinases downstream of the insulin receptor tyrosine kinase is warranted.  When insulin binds to the receptor tyrosine kinase (RTK), it phosphorlylates itself, which then leads to the binding of other proteins to the activated receptor and their phosphorylation. One of these proteins leads to changes in gene transcription.  The other, Insulin Receptor Substrate 1, IRS1, a "scaffolding protein" leads to the movement of the GLUT4 protein (Glucose transport protein) to the cell surface. These activities are shown schematically in the figure below. 

 Figure: Initial Signaling on Binding of Insulin to the Insulin Receptor

insulin signaling

After phosphorylation by the activated insulin receptor protein tyrosine kinase, IRS-1 binds phosphatidylinositol 3-kinase (PI3K) that causes phosphorylation of the 3'OH on phosphatidyl inositol (PI) in the inner leaflet of the membrane to form PI(3)P.  PI3K is a member of a family of kinases that phosphorylates pI.  The metabolic pathway centered on pI3K is one of the most mutated in human cancers.   PI(3)P in turn recruits to the membrane other inactive kinases, phosphoinositide-dependent kinase 1, PDK1 and Akt, also known as PKB.

Figure:  Phosphorylated Phosphatidylinositol derivatives

phosphorylated phosphatidylinositol derivatives

On binding of PI(3)P, PDK1 becomes an active kinase, which phosphorylates and activates Akt. The family of three Akt kinases are major Ser/Thr protein kinase that phosphorylates proteins involved in a host of cell activities, including regulation of glucose transport, cell proliferation and death.  In the insulin signaling pathway, active (phosphorylated) Akt leads to movement of the GLUT4 protein from intracellular endosomal vesicles to the cell surface, which offers a quicker way to import glucose into the cell that if Akt activated  GLUT 4 gene expression.

pi3K Pathway: Animation from Promega
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