Biomedical Engineering Reference
In-Depth Information
Figure 2
. (
a
) The phosphoinositide cycle. The abbreviations used are: PI = phosphatidylinosi-
tol; PIP = phosphatidylinositol 4-phosphate; PIP
2
= phosphatidylinositol 4,5-phosphate; PIP
3
=
phosphatidylinositol 3,4,5-phosphate; DG = diacylglycerol; IP
3
= inositol 1,4,5-triphosphate;
PI3K = phosphatidylinositol 3-kinase; PI5K = phosphatidylinositol 4-phosphate 5-kinase; PITP
= phosphatidylinositol transport protein. (
b
) The principle of fluorescent imaging experiments.
(
c
) Polarization of PIP
3
in response to a steady chemoattractant gradient (14). The curve with a
shallow gradient represents the chemoattractant distribution within a hexagonal field of view.
The curve with a sharp gradient shows the resulting distribution of the marker for PIP
3
within
the cell shown in the lower figure.
activates the Rac-GEF, P-Rex1, which in turn activates the small GTPase, Rac
(7). There is strong evidence that Rac activates PI5K (8). It has also been pro-
posed that Rac activates PI3K (9). Both of these steps create a positive feedback
loop in which synthesis of phosphoinositides stimulates the synthesis of even
more phosphoinositides. There is yet another positive feedback loop because
activation of PI5K increases the rate of synthesis of PIP
2
and its downstream
product, phosphatidic acid (PA), which is a potent activator of PI5K (10). Con-
sequently, upon receptor activation, the synthesis rates of PIP
2
and PIP
3
can rap-
idly accelerate to high levels. Such high synthesis rates can be sustained for no
more than a second because the concentration of phosphatidylinositol (PI) in the
plasma membrane is quite small (11). Depletion of PI in the plasma membrane
is prevented by the cytosolic PI transport protein (PITP), which transfers readily
available PI from the endoplasmic reticulum to the plasma membrane (12). The
PIP
2
formed by successive phosphorylation of PI is hydrolyzed by phospholi-
pase C (PLC) to diacylglycerol (DG) and cytosolic inositol 1,4,5-triphosphate
(IP
3
). Diacylglycerol is converted to PA and transferred to the endoplasmic re-
ticulum for regeneration of PI. The inositol produced by rapid dephosphoryla-
tion of IP
3
via multiple pathways (13), also participates in PI regeneration.
Recent experiments have established a causal link between localized phos-
phoinositide formation and lamellipod extension. Specifically, it has been shown
that
