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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 58

Module 2: Figure PtdIns4,5P 2 signalling

DAG + InsP 3 Ca 2+

PtdIns3,4,5P 3
Rac Rho Arf PA
PLD PA SPHK S1P

Cytoskeleton
PtdIns PtdIns4P PtdIns4,5P
2
Phagocytosis Ca 2+

Exocytosis
(Primes vesicles)
Endocytosis
(Recruits AP-2 to
form clathrin-coated pits)
Ion channels
(Agonist-induced hydrolysis of
PtdIns4,5P activates TRPV1
2
but inhibits potassium channels)

Multiple signalling functions of PtdIns4,5P 2 .
PtdIns4,5P 2 has multiple signalling functions in the plasma membrane. It is the lipid precursor used for the generation of second messengers such as
InsP 3 , diacylglycerol (DAG) and PtdIns3,4,5P 3 . It functions in the regulation of the phospholipase D (PLD) signalling pathway. In addition, PtdIns4,5P 2
can function as a messenger to control a whole variety of cellular systems, including the cytoskeleton, phagocytosis, exocytosis, endocytosis and ion
channels. All of these processes are sensitive to changes in the membrane level of this lipid.

the formation of the focal adhesion complex (Module 6: ing proteins) to endocytic vesicles to provide a scaffold to
Figure vinculin function). bind clathrin to form clathrin-coated pits (Module 4: Fig-
ure endocytosis). The PtdIns4P 5-kinase Iγ is recruited to
PtdIns4,5P 2 function in focal adhesions the plasma membrane, where it phosphorylates PtdIns4P
The Iγ isoform of PtdIns4P 5-kinase (PtdIns4P 5-K) is to PtdIns4,5P 2 , which recruits the adaptor protein AP-2
highly localized at the focal adhesion complex,where it to form the clathrin-coated pits.
is tightly bound to talin to regulate the local formation of
PtdIns4,5P 2 (Module 6: Figure integrin signalling).
PtdIns4,5P 2 regulation of phagocytosis
When macrophages engulf foreign particles, PtdIns4P 5-k-
PtdIns4,5P 2 regulation of exocytosis
inase (PtdIns4P 5-K) Iα is recruited to the plasma mem-
The synthesis of PtdIns4,5P 2 has been implicated in the brane at the phagosome cup, where it induces a local pulse
ATP-dependent processes of priming vesicles as part of of PtdIns4,5P 2 , which is then rapidly degraded by phos-
the exocytotic mechanism. The priming process seems to pholipase C (PLC) to leave behind diacylglycerol (DAG).
depend upon a number of steps that begin with the PtdIns This local formation of PtdIns4,5P 2 seems essential for the
transfer protein carrying PtdIns to the vesicle membrane early process of phagocytosis.
where it is phosphorylated to PtdIns4P by PtdIns 4-kinase The localized transient increase in PtdIns4,5P 2 may
(PtdIns 4-K) andthentoPtdIns4,5P 2 by the PtdIns4P function in the initial recruitment of actin to the phagocyte.
5-kinase (PtdIns4P 5-K). It is still not clear exactly how this
PtdIns4,5P 2 functions to prime the vesicle for exocytosis.
The ability of the neuronal Ca 2 + sensor-1 (NCS-1) to
PtdIns4,5P 2 activation of phospholipase D
facilitate exocytosis may depend on its ability to activate
Phospholipase D (PLD), which catalyses the hydrolysis
the PtdIns 4-kinase (PtdIns 4-K).
of phosphatidylcholine (PC) to generate phosphatidic acid
(PA), exists as two isoforms, PLD1 and PLD2. The PLD1
PtdIns4,5P 2 regulation of membrane trafficking and is primarily located on vesicles associated with the en-
endocytosis dosomal/lysosomal pathway, whereas PLD2 is mainly
PtdIns4,5P 2 plays a role in endocytosis by targeting found on the plasma membrane. An interaction between
adaptor protein 2 (AP2) and various clathrin-associated PtdIns4P 5-kinase α (PtdIns4P 5-Kα) and the PLDs en-
sortin proteins (CLASPs) (Module 4: Figure cargo sort- sures that there is a local generation of PtdIns4,5P 2 that

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