РІЗК/PIP 3/Akt Signaling Module

PIP2 and PI3K

The phospholipid PIP2, phosphorylated on the four and five positions of the phosphoinositol head group, is a substrate for phosphoinositide 3-kinase, or PI3K.

PI3K catalyzes the addition of a phosphate group to the three position of the phosphoinositol head group.

• The product is the phosphotidylinositol 3,4,5-triphosphate, or PI 3,4,5P3, or simply PIP3 for short.

• The phosphorylation of PIP3 is reversible and can be removed by a phosphatase to regenerate PIP2.

effect of PIP3 generation

One effect of PIP3 generation is the activation of Akt.

Akt is a kinase that phosphorylates target proteins on serine and/or threonine.

The unphosphorylated form of Akt, represented here in purple, is inactive.

Akt is activated through phosphorylation by two other protein kinases called PDK1 and mTOR.

How is AKT activated

The unphosphorylated form of Akt, represented here in purple, is inactive.

Akt is activated through phosphorylation by two other protein kinases called PDK1 and mTOR.

PH Domains and Membrane Recruitment

Akt and PDK1 both contain PH domains, which are part of the protein that binds specifically to PIP3.

Therefore, when PIP3, represented here by the orange phospholipids, is generated in a membrane, PDK1 and Akt will both become associated with a membrane.

The close proximity of PDK1 and Akt at the membrane allows PDK1 to phosphorylate Akt.

mTOR can also phosphorylate Akt to achieve maximal activity.

The active form of Akt can phosphorylate many effector proteins, which continues the signaling pathway

PH Domains and Membrane Recruitment 1

Akt and PDK1 both contain PH domains (of the protein that binds specifically to PIP3)

Therefore, when PIP3, represented here by the orange phospholipids, is generated in a membrane, PDK1 and Akt will both become associated with a membrane.

PH Domains and Membrane Recruitment 2

The close proximity of PDK1 and Akt at the membrane allows PDK1 to phosphorylate Akt.

mTOR can also phosphorylate Akt to achieve maximal activity.