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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 95

complex that then phosphorylates the interferon- The fact that the activation of PLD1 seems to depend on
regulatory factors (IFRs) IRF3 and IRF7 as described the prior activation of other signalling pathways such as
above (see step 5). the diacylglycerol (DAG)/protein kinase C (PKC) sig-
nalling cassette or the PtdIns 3-kinase signalling cassette
Nucleotide oligomerization domain (NOD) protein-like
(Module 2: Figure PLD signalling) suggests that the PLD
receptors (NLRs)
signalling pathway is not an autonomous signalling system,
9. The double-stranded RNA (dsRNA) in the cytoplasm but should be considered more as a downstream effector
can also interact with the nucleotide oligomerization of these other signalling pathways.
domain (NOD) protein-like receptors (NLRs) (see A specific N-arachidonylphosphatidylethanolamine
pink box on the right of Module 2: Figure viral re- (NAPE) phospholipase D (PLD) (NAPE PLD) functions
cognition). One of the NLRs is the Nacht domain-, to generate anandamide, which is one of the endocannabin-
Leucine-rich repeat-, and PYD-containing protein 3 oids (Module 1: Figure anandamide).
(NALP3), which is also known as cryopyrin that re- The Arf signalling pathway plays an important role in
sponds to dsRNA to activate caspase-1. The interac- the activation of PLD (Module 2: Figure Arf signalling).
tion between NALP3 and caspase-1 is facilitated by an
adaptor called apoptosis-associated speck-like protein Phosphatidic acid (PA) action
containing a CARD (ASC). The interaction between The primary messenger of the phospholipase D (PLD) sig-
these three proteins takes place in a macromolecular nalling pathway is the lipid phosphatidic acid (PA), which
complex known as the inflammasome. has a number of actions within the cell (Module 2: Figure
10. The activated caspase-1 contributes to the develop- PLD signalling). The signalling function of PA is mainly
ment of an inflammatory response by cleaving pro- directed towards the regulation of various enzymes such as
IL-1β to form the inflammatory cytokine interleukin stimulation of the target of rapamycin (TOR) and sphin-
1β (IL-1β). gosine kinase or inhibition of protein phosphatase 1. It
also plays an important role in regulating phagocytosis
(Module 4: Figure phagosome maturation).
Phospholipase D (PLD) signalling In addition to such signalling functions, a local accu-
pathway mulation of PA may also alter the physical properties
The phospholipase D (PLD) signalling pathway functions of the membrane by creating curvatures to facilitate the
by generating phosphatidic acid (PA), which acts to reg- formation of vesicles for intracellular trafficking as oc-
ulate a wide range of cellular processes. Phospholipase D curs during the COPII-mediated transport from the ER
(PLD) activation depends upon a number of mechanisms, to the Golgi (Module 4: Figure COPII-coated vesicles)
and these may vary depending on where the signalling and the COPI-mediated transport from the Golgi to the
mechanism is located within the cell. The primary mes- ER (Module 4: Figure COPI-coated vesicles).
senger produced by this signalling pathway is PA, and
phosphatidic acid (PA) action is carried out through a Phosphatidic acid (PA) metabolism
number of downstream effectors. Phosphatidic acid (PA) Two separate enzymes carry out the metabolism of phos-
metabolism occurs through different pathways that gen- phatidic acid (PA). It can be dephosphorylated to diacyl-
erate further signalling molecules such as diacylglycerol glycerol (DAG) by a PA phosphohydrolase or it can be
(DAG) and lysophosphatidic acid (LPA). partially deacylated by a phospholipase A 2 (PLA 2 ) to form
lysophosphatidic acid (LPA) (Module 2: Figure PLD sig-
Phospholipase D (PLD) activation nalling). The LPA released from the cell is a potent agonist
Mammals have two phospholipase D (PLD) genes (PLD1 on receptors of the endothelial differentiation gene (EDG)
and PLD2), both of which have splice variants. Most atten- family (Module 2: Figure sphingomyelin signalling).
tion has focused on PLD1 as a signal transducer because it
has a low basal activity that increases markedly in response
to external stimuli. On the other hand, PLD2 has a high Sphingomyelin signalling pathway
basal activity and its role in signalling is uncertain. While The sphingomyelin signalling pathway that has been im-
most of the PLD2 is located on the plasma membrane, plicated in the control of a whole host of cellular pro-
PLD1 is found predominantly on intracellular membranes cesses through the generation and function of ceramide
(e.g. Golgi, endoplasmic reticulum and endosomes), but and sphingosine 1-phosphate (S1P), which are the main
has also been located at the plasma membrane, particu- messengers operating in this signalling pathway. The ac-
larly at caveolae. The structure of the enzyme contains tion of sphingosine 1-phosphate (S1P) is complicated be-
motifs responsible for its membrane location and catalytic cause, in addition to acting internally, S1P is released from
activity (Module 2: Figure PLD isoforms). The activity cells to function as an external ligand acting on cell-surface
of PLD1 increases following stimulation of both protein receptors. This sphingomyelinase signalling pathway also
tyrosine kinase-linked receptors (PTKRs) and Gprotein- produces ceramide, another messenger that plays a signi-
coupled receptors (GPCRs) (Module 2: Figure PLD sig- ficant part in processes such as cell proliferation, apoptosis
nalling). One of the problems with trying to understand and the response of the cell to stress and injury. One of the
the signalling function of this pathway is to determine difficulties in understanding this pathway is its pleiotropic
just how these different receptors act to stimulate PLD1. effect on cells with responses that are often diametrically

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