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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 65

(Module 4: Figure scission of endocytic vesicles). Another this GAP to come off the membrane. A closely related
m
role is to control trafficking through the endoplasmic retic- GAP1 is located on the ER.
ulum/Golgi transport system (Module 2: Figure localized
inositol lipid signalling), where it is formed by at least two
Ins3,4,5,6P 4
PtdIns 4-kinases (PtdIns 4-Ks). The small GTPase ADP- Ins3,4,5,6P 4 functions as an inhibitor of the Ca 2 + -sensitive
ribosylation factor Arf-1 recruits the PtdIns 4-KIIIβ to Cl − channels (CLCAs) in epithelial cells, which regulate
the Golgi. At resting levels of Ca 2 + , this PtdIns 4-KIIIβ salt and fluid secretion, cell volume homoeostasis and elec-
is kept inactive when bound to the Ca 2 + -sensing proteins trical excitability in neurons and smooth muscle cells. It
calneuron-1 or calneuron-2. In response to a local pulse of appears to act by preventing Ca 2 + /calmodulin-dependent
Ca 2 + , the inhibitory calneurons are replaced by neuronal protein kinase II (CaMKII) from activating the channel.
Ca 2 + sensor 1 (NCS-1) that stimulates PtdIns 4-KIIIα to Ins3,4,5,6P 4 is formed by an Ins1,3,4,5,6P 5 1-phos-
begin to produce the PtdIns4P necessary for vesicle form- phatase, which is activated by Ins1,3,4P 3 (Module 2: Fig-
ation. ure inositol phosphate metabolism).
In addition, the Golgi also has a PtdIns 4-kinase α that
produces the PtdIns4P that associates with activating pro-
tein 1 (AP-1) to regulate the trafficking of clathrin-coated InsP 6
vesicles through the trans-Golgi network. There are a number of suggestions concerning the possible
messenger role of InsP 6 . Cells contain high levels of InsP 6
(approximately 15--100 μM), and much of this is prob-
PtdIns5P signalling cassette ably not in solution, but is probably attached to the phos-
PtdIns5P has been implicated in several signalling events. pholipids in membranes through electrostatic interactions
It may modulate the PtdIns 3-kinase signalling pathway with bivalent cations. The level of InsP 6 does not change
by interfering with the metabolism of the lipid messenger
much during acute stimulation, but its level can vary over
PtdIns3,4,5P 3 . It may also have a signalling role within the
the long term, as occurs during the cell cycle and during
nucleus to control the response to DNA damage. PtdIns5P cellular differentiation. The various proposed messenger
located on chromatin may provide an anchor to bind in- functions outlined below may thus depend upon highly
hibitor of growth family, member 2 (ING2), which then localized fluctuations in specific cellular compartments.
results in acetylation of the p53 tumour suppressor.
Trafficking of vesicles
Multipurpose inositol polyphosphate InsP 6 may inhibit clathrin cage assembly by binding to ad-
signalling pathway aptor protein (AP)-2 and -3. Such a role in membrane traf-
The process of inositol phosphate metabolism generates
ficking is also consistent with the observation that InsP 6
a large number of inositol phosphates (Module 2: Figure binds to synaptotagmin by competing with the inositol
inositol phosphate metabolism). Many of these are meta- lipid-binding site. It therefore seems that InsP 6 may func-
bolic intermediates, but some have been implicated in a tion as a negative regulator of endocytic vesicle traffic.
variety of control functions: Such a possibility may explain the observation that
GRAB, which is a guanine nucleotide exchange factor that
acts on Rab3A, interacts with InsP 6 kinase which converts
Ins1,4P 2
There is some evidence to suggest that Ins1,4P 2 may func- InsP 6 into InsP 7 .
tion within the nucleus to activate DNA polymerase. This
inositol phosphate has also been implicated in Ca 2 + sig- Endocytosis
nalling and cardiac hypertrophy. In insulin-secreting β-cells, InsP 6 appears to promote dy-
namin I-mediated endocytosis through a mechanism that
depends upon protein kinase C (PKC), which may act
Ins1,3,4P 3
to inhibit the phosphoinositide phosphatase synaptojanin,
This inositol phosphate has an important signalling func-
thereby raising the level of PtdIns4,5P 2 that has been im-
tion as a negative regulator of the Ins1,3,4,5,6P 5 1-phos- plicated in vesicle dynamics.
phatase (Module 2: Figure inositol phosphate metabol-
ism) that controls the level of Ins3,4,5,6P 4 , which is an Regulation of Ca 2 + channels
-
inhibitor of Ca 2 + -sensitive Cl channels.
InsP 6 is present in many brain regions and appears to be
elevated following neural activity. It may act by stimulat-
Ins1,3,4,5P 4 ing adenylyl cyclase to produce cyclic AMP, which then
This inositol phosphate, which is formed by phosphorylat- increases the activity of L-type Ca 2 + channels. Alternat-
ing Ins1,4,5P 3 , has been implicated in the control of Ca 2 + ively, it may activate L-type Ca 2 + channels through an
entry into cells. However, its mode of action is unknown. inhibition of protein phosphatases. In vascular smooth
Some clues concerning its action may come from the iden- muscle cells, InsP 6 appears to act through a protein kinase
tification of GAP1 IP4BP , which is one of the GTPase- C (PKC)-dependent pathway.
activating protein (GAP) family (Module 2: Table mono-
meric G protein toolkit). GAP1 IP4BP normally associates Regulation of gene transcription
with the plasma membrane. When Ins1,3,4,5P 4 binds to Studies on yeast have revealed that ARG82, which is an
the membrane-anchoring domain of GAP1 IP4BP , it causes Ins1,4,5P 3 6-kinase that phosphorylates Ins1,4,5P 3 within

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