Please wait while the transcript is being prepared...
I am speaking today about the PI3K signaling pathway in cancer.
This is one of the most commonly activated and mutated pathways in cancer,
and we believe it plays an important role in the development of cancer and offers us
the opportunity to develop drugs
that inhibit this pathway, ought to be very useful in treatments.
PI3 kinase is an important signaling pathway in normal physiology.
It regulates metabolism, cell growth,
cell migration, and cell survival.
One of its key functions is regulation of metabolism and glucose homeostasis
because it's the most important downstream effector pathway that
is activated by the insulin and IGF-1 molecules.
The way this works is insulin or IGF-1 bind to a receptor,
either the insulin receptor or IGF-1 receptor,
and this causes the activation of the receptor.
The activated receptor phosphorylates
a whole variety of substrates including the IRS molecules.
Phosphorylation of these molecules causes their recruitment
to an activation of a variety of intracellular signaling molecules.
For the purpose of this talk,
the most important one of these is PI3 kinase.
PI3 kinase is an enzyme that consists of two sub-units,
a regulatory sub-unit which in this case is an 85 kilodalton sub-unit,
and a catalytic subunit, 110 kilodaltons.
This is a big family,
but these are the most commonly studied,
the class 1 kinases.
What this enzyme does is it phosphorylates phosphatidylinositol
on the three position which causes the formation of PIP3.
PIP3, which becomes phosphorylated in other positions,
the four and five position,
binds to a whole variety of proteins in the cell that have PH domains.
It binds to the phosphorylated phosphatidylinositol, PIP3, 4 or 5,
and causes it to dock to the plasma membrane
where it becomes activated by phosphorylation.
There are many such targets of
the phosphorylated phosphatidylinositols but the one that is
most well defined and most known to be important in cancer is the Akt kinase.
Akt kinase gets activated by phosphorylation after it binds to the membrane.
Phosphorylation on a serine at 473 and a threonine at 308, and Akt then
becomes activated and phosphorylates a whole variety
of substrates that are important in preventing cell death,
inducing cell growth, regulating metabolism, and inducing translation.
This whole pathway is down-regulated by a variety of
negative regulatory mechanisms including the PTEN protein.
The PTEN protein is a phosphatase that
de-phosphorylates the phosphatidylinositolphosphates on the three position,
thus turning off the pathway.
In the cell, the PI3 kinase pathway is regulated by