PI3K Pathway

Phosphoinositide 3-Kinase enzyme

It is a signal transduction system that connects oncogenes and multiple receptor classes to many cellular functions such as cell survival, proliferation and differentiation. The key enzyme family in this pathway is PI3Ks (Phosphoinositide 3-Kinases) which transducer signals from various growth factors and cytokines into intracellular messages by generating phospholipids. These phospholipids activate the serine- threonine protein kinase AKT (also known as protein kinase B (PKB)) and other downstream effector pathways.

PIP2 (PtdIns (4,5) P₂) à PIP3 (PtdsIns (3,4,5) P₃)

The enzyme family is classified into three classes based on the structural characteristics and substrate specificity:

Class I enzyme: à These enzymes are activated directly by the cell surface receptors. They are further classified into two sub classes. i.e. class IA and class IB.

Class IA enzyme à they are heterodimers consisting of a P110 catalytic subunit and p85 regulatory subunit.

            p85 regulatory subunit mediates receptor binding, activation and localization of enzyme.

This subunit directly interacts with tyrosine phosphate motif of activated receptor (eg: platelet growth factor receptor) or to adapter proteins associated with receptor (Eg: IRS1)

Activated P110 catalytic subunit generates phosphoinositide 3,4,5 triphosphate which further activates multiple downstream signalling pathway.

Class IB enzyme à It’s also a heterodimer with p110γ catalytic subunit and p101 regulatory subunit. Apart from this they also contain some adapter proteins such as p84, p87.

P110γ subunit is activated by GPCRs through interaction of regulatory subunit with Gβγ subunit of trimeric G proteins. P110γ is expressed in leukocytes but also found in heart, pancreases, liver, and skeletal muscles.

Class II enzyme: à

It consists of only a single catalytic subunit. Phosphatidylinositol 4-phosphate (PtdsIns4P) is used as the substrate.

It is found in three isoforms: a) PI3KC2α b) PI3KC2β c) PI3KC2γ

And these can be activated by receptor tyrosine kinases, cytokine receptors, and integrins.

But still their specific role in cellular function remains unclear.

Class III enzyme: à

 It consists of a single catalytic subunit VPS34 (Homologue of the yeast vacuolar protein sorting associated protein 34). It’s also known as PIK3C3 which only producesPtdIns3P, which is an important regulator of membrane trafficking.

The subunit function as a nutrient regulated lipid kinase that mediates signalling throught mTOR (mammalian target of rapamycin).

The negative regulator of this PI3K pathway is a tumor suppressor protein called PTEN (Phosphotase and Tensin homologue). PIP3 (PtdsIns (3,4,5) P₃) is the key second messenger that drives several downstream signalling cascades that regulate cellular processes. The cellular levels of PIP3 are tightly regulated by the opposing activity of PTEN. PTEN functionally antagonizes PI3K activity through its intrinsic lipid phosphatase activity that reduces the cellular pool of PIP3 by converting PIP3 back to PtdIns (4,5) P₂.

Read More