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.