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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 57

Module 2: Figure localized inositol lipid signalling

a l P s m a m e m a r b n e Endocytosis
PtdIns3,4,5P PtdIns4,5P 2 PtdIns4P PtdIns4,5P
3 2
P I P I K
DAG
SJ1
PtdIns
PKB PKC Ins1,4,5P
3 PtdIns4P
Actin polymerization
Protein Calcium Ion channel regulation C o e t a v d e e l c i s
phosphorylation signalling Exocytosis
Phagocytosis
a r T n - s G i g l o
network (TGN)
Ca 2+ T e r o n i l c y c g h V P S 3 4
endosome
Golgi T o G i g l o E e y l r a n d o s o m e
PtdIns4P PtdIns
PtdIns PtdIns3P
Phosphatidic acid
PtdIns4P PtdIns PtdIns3,5P 2
E n d o a l p s m c i PtdIns Late endosome
c i t e r u l u m PtdIns3P (MVE)
PtdIns4P
PtdIns4,5P 2
Autophagic PtdIns3P
vesicle PtdIns3,5P 2
PtdIns3,4,5P
3 Lysosome
Multiple roles of inositol lipids in cell regulation
Inositol lipids located in the plasma membrane and in various organelles have multiple roles in cell regulation. At the plasma membrane, they generate
various signalling molecules, whereas in cellular organelles they orchestrate many of the events associated with membrane and protein trafficking.

• PtdIns4,5P 2 regulation of membrane trafficking and en- catalysing the exchange of GDP for GTP. The active G
docytosis proteins can then have a number of functions. For example,
• PtdIns4,5P 2 regulation of exocytosis one function of Rac-GTP is to activate actin polymeriz-
• PtdIns4,5P 2 activation of phospholipase D ation (Module 2: Figure Rac signalling). Similarly, Cdc42
• PtdIns4,5P 2 regulation of ion channels and exchangers also stimulates actin remodelling (Module 2: Figure Cdc42
• PtdIns4,5P 2 function in focal adhesions signalling). The consequence of this remodelling varies de-
• PtdIns4,5P 2 regulation of phagocytosis pending on which G protein is operating. For example,
the Cdc42 and Rac polymerization of actin results in the
PtdIns4,5P 2 regulation of actin remodelling formation of filopodia and ruffles respectively (Module 4:
There are a number of cellular processes, such as chemo- Figure actin remodelling).
taxis, locomotion, phagocytosis, shape change and cy- The formation of PtdIns4,5P 2 contributes to actin
tokinesis, where there are rapid changes in the cytoskeleton remodelling by acting on a number of the mo-
in response to external stimuli such as growth factors and lecules that control actin polymerization such as the
cytokines. Inositol lipids play a significant role in transmit- Wiskott-Aldrich syndrome protein (WASP) and the re-
ting information from the plasma membrane to a variety of lated Wiskott-Aldrich syndrome protein (WASP) verpro-
cell signalling systems (Module 2: Figure localized inositol lin homologous (WAVE) proteins. WASP and WAVE relay
lipid signalling). The formation of PtdIns4,5P 2 functions to information from the upstream signalling elements to the
control actin remodelling (Module 4: Figure actin remod- downstream cytoskeletal regulators. Perhaps the most im-
elling). Its main actions are to uncap the barbed end of actin portant example of the latter is the actin-related protein 2/3
filaments and to facilitate actin nucleation and polymeriz- (Arp2/3) complex (containing seven strongly associated
ation by controlling a variety of actin regulatory proteins. subunits of which two are the actin-related proteins Arp2
A critical component of the signalling network is the Rho and Arp3) that is responsible for catalysing the polymer-
family of monomeric G proteins (Arf, Rho, Cdc42 and ization of actin. PtdIns4,5P 2 appears to have two actions.
Rac) that relay information from various signalling path- It binds to and activates WASP and to Scar and thus con-
ways such as the PtdIns 3-kinase signalling pathwaytothe tributes to the relay of information to Arp2/3. In addition,
effector molecules that are directly responsible for remod- it can alter the activity of various proteins that modify the
elling the actin network. One of the signalling molecules structure of actin. For example, it is an indirect activator
is PtdIns4,5P 2 . of Cdc42 and it may loosen the gelsolin caps on the end of
The signalling cascade begins when external signals act- the barbed ends, opening up new sites for actin polymeriz-
ing through guanine nucleotide exchange factors (GEFs) ation. The PtdIns4,5P 2 may also induce a conformational
stimulate members of the Rho family of G proteins by change in vinculin that enables it to bind to talin during

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