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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 48

signalling pathways of compensatory hypertrophy and is Ins1,4,5,6P 4 3-kinase
up-regulated in human colorectal cancer. Step 11 in Module 2: Figure inositol phosphate metabol-
ism.
Inositol monophosphatase
Steps 3 in Module 2: Figure inositol phosphate metabol- Ins1,3,4,5,6P 5 /InsP 6 3-phosphatase
ism. The free inositol that is formed by this enzyme is Steps 12 in Module 2: Figure inositol phosphate metabol-
then used to resynthesize PtdIns, which is returned to ism. This enzyme is also known as the multiple inositol
the plasma membrane, where it can be reused to function phosphate phosphatase (MIPP). Its function is somewhat
as the precursor for the phosphoinositide signalling lip- unclear because it is located within the lumen of the ER,
ids (Module 2: Figure phosphoinositide metabolism). This apparently insulated from its two substrates.
inositol monophosphatase is inhibited by lithium (Li ),
+
which thus acts to reduce the supply of inositol (Module Ins1,3,4,5,6P 5 2-kinase
2: Figure InsP 3 /DAG recycling). This ability of Li + to Step 13 in Module 2: Figure inositol phosphate metabol-
lower the level of inositol is the basis of an inositol de- ism. The production of InsP 6 occurs primarily through the
pletion hypothesis to account for its action in controlling phosphorylation of Ins1,3,4,5,6P 5 by a 2-kinase.
manic-depressive illness.
InsP 6 kinase
Ins1,4,5P 3 3-kinase Steps 14 in Module 2: Figure inositol phosphate meta-
Step 4 in Module 2: Figure inositol phosphate metabolism. bolism. This kinase adds an additional phosphate to
This kinase is one of the major pathways for metabolizing that already present on the 5-position to produce InsP 7
the second messenger Ins1,4,5P 3 . There are three isoforms (PP-InsP 5 ). This kinase can run in reverse and is thus po-
of this enzyme (InsP 3 3-kinase A, B and C). Both type tentially capable of reforming ATP. The same enzyme may
A and type B are activated by Ca 2 + /calmodulin, with the act on Ins1,3,4,5,6P 5 to produce PPInsP 4 . There are three
type B being the most sensitive. This enzyme is also sens- isoforms (InsP 6 K1--InsP 6 K3). InsP 6 K2 has been implic-
itive to other signalling pathways in that both forms are ated in the action of interferons on cell growth and apop-
inhibited by PKC. On the other hand, protein kinase A tosis.
(PKA) activates type A but inhibits type B.
Diphosphoinositol phosphate phosphohydrolase
Inositol polyphosphate 4-phosphatase (DIPP)
Steps 5 in Module 2: Figure inositol phosphate metabol- Steps 15 in Module 2: Figure inositol phosphate metabol-
ism. A multifunctional phosphatase capable of dephos- ism. This enzyme dephosphorylates both PP-InsP 5 (InsP 7 )
phorylating both Ins3,4P 2 and Ins1,3,4P 3 ,aswellasthe and [PP] 2 -InsP 4 (InsP 8 ), during which it removes the β-
inositol lipid PtdIns3,4P 2 . This enzyme might be a regu- phosphate from the diphosphate groups.
lator of cell proliferation, since it is absent in hyperprolif-
erative megakaryocytes that lack the transcription factor PP-InsP 5 kinase
GATA-1. Step 16 in Module 2: Figure inositol phosphate metabol-
ism. This kinase adds a further phosphate to PP-InsP 5 to
Inositol polyphosphate 3-phosphatase form [PP] 2 -InsP 4 , but the positional specificity of the lat-
Steps 6 in Module 2: Figure inositol phosphate metabol- ter remains to be established. Like the InsP 6 kinase,this
ism. A multifunctional phosphatase capable of dephos- enzyme is capable of forming ATP by running in a reverse
phorylating both Ins1,3P 2 and PtdIns3P. mode.

Ins1,3,4P 3 6-kinase Mammalian inositol phosphate multikinase (mIPMK)
Step 7 in Module 2: Figure inositol phosphate metabolism. Steps 17 in Module 2: Figure inositol phosphate metabol-
ism. This mammalian inositol phosphate multikinase (mI-
PMK) is a multifunctional kinase capable of the following
Ins1,3,4,6P 4 5-kinase
Step 8 in Module 2: Figure inositol phosphate metabolism. phosphorylations:
• Ins4,5P 2 → Ins1,4,5P 3
Ins3,4,5,6P 4 1-kinase • Ins1,4,5P 3 → Ins1,3,4,5P 4
Step 9 in Module 2: Figure inositol phosphate metabolism. • Ins1,3,4,5P 4 → InsP 5
This enzyme is responsible for inactivating the Ins3,4,5,6P 4 • InsP 5 → PP-InsP 4
that regulates chloride channels. It is an unusual enzyme
in that it has alternative positional specificity (5/6-kinase Inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2 +
activity against Ins1,3,4P 3 ). The enzyme is the same as the signalling cassette
Ins1,3,4,5,6P 5 1-phosphatase. This signalling cassette uses the second messenger inos-
itol 1,4,5-trisphosphate (InsP 3 ) to mobilize Ca 2 + from in-
Ins1,3,4,5,6P 5 1-phosphatase ternal stores. When external stimuli engage receptors on
Step 10 in Module 2: Figure inositol phosphate metabol- the cell surface, they activate the enzyme phospholipase C
ism. The enzyme is equivalent to the Ins 3,4,5,6P 4 1-kinase. (PLC), which hydrolyses PtdIns4,5P 2 to yield InsP 3 and

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