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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 44

Module 2: Figure PI 3-K family

Class IA
p85 p85 SH3 P BCR P SH2 p110 binding SH2
p55 p50 p P SH2 p110 binding SH2
PIP
2 PIP 3
Regulatory
subunits
p110 p110 p110 p85 Ras C2 Helical Kinase
Catalytic subunits

Class IB
p101 p84 Homolgy I Homolgy II
Regulatory p110 Ras C2 Helical
subunits Kinase
Catalytic subunit

Class II
PI3KC2
PI3KC2 P P Ras C2 Helical Kinase PX C2
PI3KC2
Catalytic subunits
Heat domains Wd40 domains CaM-binding Class III
p150 Kinase domain Accessory
domain
Regulatory PIK3C3 (hVPS34) C2 Kinase
subunit
Catalytic subunit

The regulatory and catalytic subunits of the PtdIns 3-kinase family.
The family of PtdIns 3-kinase is divided into three classes. The kinase domain (shown in yellow) phosphorylates PtdIns4,5P 2 (PIP 2 ) to form the lipid
messenger PtdIns3,4,5P 3 (PIP 3 ). The domain structures of the regulatory and catalytic subunits are described in the text. Information for this figure
was taken from Hawkins et al. 2006.

PtdIns4P 5-kinase Iβ exocytosis, the PLD signalling pathway (Module 2: Figure
This isoform is found on membranes surrounding the nuc- PLD signalling) and the permeability of ion channels.
leus. The PtdIns4P 5-Kα has an additional role in that it can
phosphorylate PtdIns3,4P 2 to form the lipid second mes-
senger PtdIns3,4,5P 3 (Step 8 in Module 2: Figure phos-
PtdIns4P 5-kinase Iγ phoinositide metabolism).
The PtdIns4,5P 2 function in focal adhesions depends upon
a spliced form of this enzyme, which is targeted to focal
adhesions by interacting with talin (Module 6: Figure in- PtdInsP kinase II
tegrin signalling). Talin contains a FERM domain,which is This enzyme, which is found in the cytosol, endoplas-
mic reticulum and nucleus, but not in the plasma mem-
used to bring PtdIns4P 5-kinase Iγ into the adhesion com-
brane, is a PtdInsP 4-kinase capable of phosphorylat-
plex. Similarly, this isoform plays a major role the control
of endocytosis (Module 4: Figure endocytosis). ing both PtdIns3P and PtdIns5P to produce PtdIns3,4P 2
and PtdIns4,5P 2 respectively (Steps 6 in Module 2: Figure
This Type I enzyme can be regulated by two separate
phosphoinositide metabolism).
mechanisms. Firstly, its activity is stimulated by phospha-
tidic acid (PA) that is formed either by the phospholipase
D (PLD) signalling pathway where phosphatidylcholine PtdInsP kinase III (PIKfyve)
(PC) is hydrolysed by phospholipase D (Module 2: Fig- This type III PtdInsP kinase, which is known as
ure PLD signalling) or by the phosphorylation of diacyl- PhosphoInositide Kinase for five position containing
glycerol (DAG) by diacylglycerol kinase (DAG) kinase aFyve finger (PIKfyve), phosphorylates PtdIns3P to
(Module 2: Figure InsP 3 /DAG recycling). Secondly, en- PtdIns3,5P 2 (Step 4 in Module 2: Figure phosphoinos-
zyme activity can be enhanced by small monomeric G itide metabolism). Despite being classified as a PtdInsP
proteins such as Rho (Module 2: Figure Rho signalling). kinase, this kinase may also phosphorylate PtdIns on the
During its activation, PtdIns4P 5-kinase Iα translocates to 5-position to form PtdIns5P (see Step 3). This PIKfyve
the plasma membrane through an activation mechanism kinase has a FYVE domain to target it to endomembranes
that is dependent upon Rac and Rho. This G protein reg- where it functions in the PtdIns3,5P 2 signalling cassette
ulation results in the localized synthesis of PtdIns4,5P 2 , (Module 2: Figure PIKfyve activation).
which then acts as a second messenger for the PtdIns4,5P 2 Mutations in PIKfyve have been linked to
signalling cassette. For example, it can influence a variety Franc¸ois-Neetens Mouchet´ ee fleck corneal dystrophy
of proteins to regulate processes such as actin remodelling, (CFD).

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