Hello, this is Glenn Prestwich,
I'm a professor of medicinal chemistry
at the University of Utah, and
I'm going to be talking today about the
use of chemical probes for visualizing and
manipulating phosphoinositide and
phospholipid signaling in cells.
Lipids are important mediators
of cellular communication,
they can occur both outside the cells in
the extracellular medium, or inside cells.
The external messengers, such as
lysophosphatidic acid are important cell
mitogens and control cell migration and
whereas messengers that are inside the
cells, such as the phosphoinositides and
other phospholipids on the inner leaflet,
recruit proteins and
the complexes then end up controlling
cell shape, cytoskeletal rearrangements,
cell survival, cell differentiation and
metabolic events within the cell.
occur in eight chemical forms.
There is the phosphatidylinositol itself,
with no additional phosphates on
the myo-inositol head group attached
through a phosphodiester bond to
a diacylglycerol moiety, or
you can have a single phosphate,
as in the phosphomonoesters PI(3)P,
PI(4)P and PI(5)P.
You can have three different forms of
phosphoinositide bisphosphates such as
PI(4,5)P2, PI(3,4)P2 and PI(3,5)P2, or
a single trisphosphate PI(3,4,5)P3.
For additional information on the
synthesis of the native phosphoinositides
and their affinity probes, and for
the uses of these, I would refer
the listener to review articles as
shown in the bottom of the slide.
In Salt Lake City we view phosphoinositide
signaling in a slightly different way,
we view it in three dimensions, where the
phosphoinositide energy requiring kinase
is using ATP to put additional phosphates
onto the phosphoinositide head-group and
ultimately getting to
Mount Supreme up there.
PIP3 is the most highly phosphorylated and
most highly interactive phosphoinositide,
giving rise to mitogenic effects
in cell growth, carcinogenesis,
abnormal as well as normal responses in
inflammatory and immune response, and
in normally controlling
the insulin response.
In addition to the kinases
there are phosphatases which
remove phosphate groups,
as well as phospholipases.
We'll talk more about these and how to
manipulate those later on in this talk.