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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 56

Module 2: Figure PKC structure and activation

DAG Ca 2+ ATP PDK1
PS P P P Conventional (cPKC)
C1A C1B C2 C3 C4 (
PS P P P
Novel (nPKC)
C2-like C1A C1B C3 C4
(
PS P P
C1 C3 C4 Atypical (aPKC)
(
AGONIST
Plasma membrane
R
PLC
DAG C1
PtdIns4,5P Translocation
2 C 2 C4
InsP
3 P P
P
Substrate
C1
C2 P C 2 C4
2+ C4 P P P
Ca C1 P P PS P
Substrate Substrate
cPKC

Structure of PKC isoforms and activation mechanism of the conventional protein kinase C (cPKC) isoforms.
The nine genes that code for protein kinase C (PKC) fall into three families. Conventional PKCs (cPKCs) have a domain structure that has an N-terminal
pseudosubstrate (PS) domain followed by regulatory domains (C1 and C2), which are responsible for binding the diacylglycerol (DAG) and Ca 2 +
responsible for membrane targeting, an ATP-binding C3 domain and the C4 catalytic domain. The C1 region is present as a tandem repeat (C1A
and C1B). The PS domain has an autoinhibitory function in that it associates with the catalytic site on C4, thus preventing it from phosphorylating its
substrates. Novel PKCs (nPKCs) have a similar domain structure, except that they have a C2-like domain that does not bind Ca 2 + . Atypical (aPKCs)
also lack a C2 domain, and the C1 domain is small and fails to bind DAG. The illustration at the bottom indicates how cPKC is activated, as described
in the text.

Phosphoinositide lipid signalling molecules PtdIns4,5P 2 signalling cassette
Some of the phosphoinositides derived from the metabol- The phosphoinositide PtdIns4,5P 2 is widely distributed
ism of PtdIns (Module 2: Figure phosphoinositide meta- throughout the cell. Not only is it found in the plasma
bolism) have important signalling functions that are of- membrane, but also it occurs in the Golgi, endosomes,
ten located in specific cellular membranes (Module 2: Fig- endoplasmic reticulum (ER) and within dense structures
ure localized inositol lipid signalling). One of the most within the nucleus. This lipid has two main roles. Firstly, it
versatile systems is the PtdIns4,5P 2 signalling cassette. is hydrolysed to form InsP 3 and diacylglycerol (DAG) or it
PtdIns4,5P 2 is the precursor used to generate second mes- can be phosphorylated further to form the lipid messenger
sengers such as InsP 3 , DAG and PtdIns3,4,5P 3 . The latter PtdIns3,4,5P 3 (Module 2: Figure localized inositol lipid
is a particularly important messenger because the forma- signalling). Secondly, PtdIns4,5P 2 can also function as a
tion of PtdIns3,4,5P 3 drives the PtdIns 3-kinase signalling lipid messenger (Module 2: Figure PtdIns4,5P 2 signalling).
system that controls a great variety of cellular processes Such a signalling role is supported by the observation that
(Module 2: Figure PtdIns 3-kinase signalling). In addition, cell stimulation can result in highly localized increases in
PtdIns4,5P 2 is a messenger in its own right in that local- PtdIns4,5P 2 . The localized formation of this lipid messen-
ized formation of this lipid can control endocytosis, actin ger can be activated by the monomeric G proteins and in
remodelling, ion channels and phagocytosis (Module 2: particular the family of Rho proteins. For example, Rac
Figure localized inositol lipid signalling). and Rho can function to target PtdIns4P 5-kinase I to the
There is increasing evidence that some of the other plasma membrane. In addition, Rho-GTP can activate this
lipids may also play signalling roles as described in kinase directly to form PtdIns4,5P 2 (Module 2: Figure Rho
the PtdIns3P signalling cassette,the PtdIns4P sig- signalling).
nalling cassette,the PtdIns5P signalling cassette and the There is increasing evidence that a variety of cellular
PtdIns3,5P 2 signalling cassette.Inthe caseofthe lat- processes are activated in response to a change in the level
ter, the PtdIns3,5P 2 in the late endosome activates the of this lipid:
TRPML1 channels to produce the Ca 2 + signals neces-
sary to trigger the membrane fusion events that form the
lysosomes. • PtdIns4,5P 2 regulation of actin remodelling

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