Page 55 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 55

Phospholipase Cζ (PLCζ) inducing the translocation of cPKCs to the plasma mem-
Phospholipase Cζ (PLCζ) has a restricted expression in brane.
that it is only found in mammalian sperm. PLCζ lacks The activation of the cPKC isoforms follows a set
the N-terminal PH domain (Module 2: Figure PLC struc- sequence of events that begins with the hydrolysis of
ture and function), which means that there is no obvious PtdIns4,5P 2 to form DAG and inositol 1,4,5-trisphosphate
mechanism for it to bind to phospholipids. PLCζ has a (InsP 3 ). The InsP 3 releases Ca 2 + , which initiates the activa-
sensitivity to Ca 2 + that is 100-fold greater than that of tion process by binding to the C2 domain to induce a con-
PLCδ1. Both the C2 and the tandem EF-hands are neces- formational change that greatly enhances the membrane
sary for PLCζ to hydrolyse PtdIns4,5P 2 to generate the affinity of cPKC and thus promotes its translocation to
InsP 3 that plays a central role in sperm-induced oocyte ac- the membrane where it is activated when it makes contact
tivation during fertilization (Module 8: Figure mammalian with DAG. The pseudosubstrate (PS) domain swings away
fertilization). from the active site, which is now free to phosphorylate its
substrates.
Diacylglycerol (DAG)/protein kinase C (PKC) The nPKCs, which are also activated by DAG, have
signalling cassette a much slower activation process because the Ca 2 + -
The diacylglycerol (DAG) that is formed when dependent facilitation of membrane translocation is ab-
PtdIns4,5P 2 is hydrolysed by phospholipase C (PLC) re- sent.
mains within the plane of the membrane where it acts as a
lipid messenger to stimulate some members of the protein
kinase C (PKC) family (Module 2: Figure InsP 3 and DAG Protein kinase Cζ (PKCζ)
formation). This PKC family contains a number of iso- This is one of the atypical PKC isoforms (aPKC),
forms with diverse structures and activation mechanisms. which fails to respond to diacylglycerol (DAG) or Ca 2 + ,
The PKC signalling function is equally diverse, and it has but is sensitive to low levels of ceramide (Module 2:
proved difficult to pin down its precise function in the Figure sphingomyelin signalling). PKCζ is also activ-
regulation of specific cellular processes. ated following phosphorylation by kinases from other
signalling pathways. For example, PKCζ is activated
by phosphoinositide-dependent kinase 1/2 (PDK1/2)
Protein kinase C (PKC) (Module 2: Figure PtdIns 3-kinase signalling). In some
The protein kinase C family has been divided into three cells, it is responsible for activating nuclear factor κB(NF-
subgroups (Module 2: Figure PKC structure and activa- κB). PKCζ can also phosphorylate the glucose transporter
tion):
in skeletal muscle (Module 7: Figure skeletal muscle E-C
coupling).
• Conventional PKCs (cPKCs: α, β1, β2and γ) contain
C1 and C2 domains
• Novel PKCs (nPKCs: δ, ε, η and θ) contain a C1 and a
Protein kinase Cθ (PKCθ)
C2-like domain
Protein kinase Cθ (PKCθ) is one of the novel PKCs
• Atypical PKCs (aPKCs: ζ , ι and λ) contain a truncated
(nPKCs) that plays an important role in lymphocyte ac-
C1 domain
tivation where it is concentrated in the central region of
theimmunological synapse (Module 9: Figure immunolo-
The activation of these different PKC families is com-
plex in that it depends on a number of processes such gical synapse structure). The PKCθ functions by activating
the nuclear factor κB(NF-κB) signalling pathway by phos-
as priming, translocation and association with scaffolding
phorylating the scaffolding protein CARMA1 (Module 9:
proteins. The priming process is driven by a sequence of
Figure TCR signalling).
multisite phosphorylation events that have to occur before
the enzyme can perform its signalling function. The newly
synthesized proteins are inactive and undergo a prim- PKC signalling functions
ing process that begins when phosphoinositide-dependent The different PKC isoforms function to regulate a wide
protein kinase 1 (PDK1), which is part of the PtdIns 3-k- range of cellular processes:
inase signalling pathway, phosphorylates a site in the C4
domain (Module 2: Figure PKC structure and activation).
This is then followed by intramolecular autophosphoryla- • PKCε functions to control the N-type Ca 2 + channel
tion reactions of two further sites in the C-terminal tail. (Module 3: Figure Ca V 2 channel family).
The primed enzyme is now ready to perform its signalling • PKC is one of the kinases responsible for phosphorylat-
function by responding to both diacylglycerol (DAG) ing the transcription factor p53 (Module 4: Figure p53
and Ca 2 + . The cPKCs and most of the nPKCs are lipid- domains).
sensitive enzymes in that they are activated by DAG that • PKC functions to regulate the calmodulin (CaM)-
binds to the C1 domain. This C1 domain is also respons- binding properties of proteins such as neuromodulin
ible for binding the tumour-promoting phorbol esters. In and neurogranin.
the case of the cPKCs, Ca 2 + also plays an important role • Protein kinase C functions in the modulation of Ca V 1.2
as a cofactor that binds to the C2 domain to increase its L-type channels from heart muscle (Module 3: Figure
affinity for acidic phospholipids and is thus responsible for Ca V 1.2 L-type channel).

C 2012 Portland Press Limited www.cellsignallingbiology.org