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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 98

Module 2: Figure sphingomyelin signalling

TNF Growth factors N S1P LPA
Hormones P
EDG
ABCC1 receptors
Neutral CDase G q
N SMase N N SPHK Ca 2+ PI 3-K
P OH OH DAG 8 Ras
SM FAN
N 3 Cer Sph ERK1/2
Golgi 4 N S1P
P
2 Phospho- DAG InsP 3
SPPs S1P lyase ethanolamine
OH 6 Ca 2+
N
Cer
Ionizing PKB PKC
Desaturase radiation ROS CAPPs
CAPK
5 JNK ERK1/2 CaMKII
ER 7 PKC
N
dhCer
Acidic Cathepsin D 9
SMase
CerS 1
N P N N Apoptosis Survival
dhSph N
Cell cycle Proliferation
OH
SPT SM Cer arrest
Anti-inflammatory
Lysosome Senescence responses
Serine + palmitate
The sphingomyelin signalling pathway.
A number of stimuli can activate the neutral or acidic sphingomyelinases (SMase) to hydrolyse sphingomyelin (SM) to ceramide (Cer), which is then
converted into sphingosine (Sph) by ceramidase (CDase). The sphingosine is converted into sphingosine 1-phosphate (S1P) by a sphingosine kinase
(SPHK), which is sensitive to other signalling pathways using messengers such as Ca 2 + , diacylglycerol (DAG), cyclic AMP (cAMP) and extracellular-
signal-regulated kinase 1/2 (ERK1/2). Ceramide can activate a number of targets, and some of these can activate apoptosis. On the other hand, S1P
can promote survival and proliferation by passing out of the cell, where it functions as an external ligand to activate endothelial differentiation gene
(EDG) receptors.

the membrane and is free to diffuse both into and out of growth factor and hormone receptors that elevate second
the cell (see later). The SPHK is activated by a number messengers such as Ca 2 + , DAG, ERK1/2 or cyclic AMP
of signalling pathways using messengers such as Ca 2 + , that act by stimulating SPHK. In the absence of these sig-
DAG, cyclic AMP and ERK1/2 that are produced by nals, the main messenger will be ceramide, but this will
signalling pathways activated by growth factors and switch over to S1P if the SPHK is activated. This inter-
hormones. Ceramide can also be phosphorylated by relationship between ceramide and S1P has led to a cer-
a ceramide kinase to form ceramide 1-phosphate, for amide/S1P rheostat model, where a balance between these
which there is no apparent function. two messengers is thought to determine cell fate. In gen-
5. A variety of stress stimuli, such as ionizing radiation, eral, ceramide seems to tip the balance in favour of cell
UV irradiation and reactive oxygen species (ROS) act cycle arrest, senescence and apoptosis, whereas S1P pro-
by stimulating the acidic sphingomyelinases (SMases) motes survival and proliferation (Module 2: Figure sphin-
localized in lysosomes to hydrolyse sphingomyelin gomyelin signalling). The different outcomes controlled
(SM) to form ceramide (Cer) (Module 2: Figure sphin- by these two messengers may depend on their ability to
gomyelin signalling). activate separate signalling cascades.
6. S1P is metabolized via two separate pathways: it can
be converted back into sphingosine by a sphingosine 7. The ceramide formed at the plasma membrane or
1-phosphate (S1P) phosphatase (SPP) or it can be in the lysosomes acts on a number of targets such
cleaved by an S1P lyase to give palmitaldehyde and as ceramide-activated protein kinase (CAPK), protein
phosphoethanolamine. The lyase has a 20-amino-acid kinase Cζ (PKCζ), cathepsin D and ceramide-activated
transmembrane domain that positions the enzymes in protein phosphatases (CAPP), such as PP1 and PP2A.
cellular membranes. Most of these ceramide-sensitive targets act to promote
cell cycle arrest and apoptosis either directly or indir-
The sphingomyelinase signalling pathway is thus sens- ectly. For example, the cathepsin D converts Bid into
itive to external signals at a number of discrete steps. The tBid to promote apoptosis (see Step 3 in Module 11:
production of ceramide is accelerated by receptors sens- Figure apoptosis). On the other hand, the CAPPs such
itive to cytokines such as TNFα or to various stress sig- as PP2A can dephosphorylate various components that
nals such as ionizing radiation and reactive oxygen species are used by the EDG receptors to drive cell survival
(ROS). The formation of S1P can also be enhanced by and proliferation. For example the dephosphorylation

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