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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 99

of protein kinase B (PKB) not only prevents it from The intracellular action of S1P is not as well defined,
inhibiting apoptosis but it will also reduce its ability to mainly because it is often difficult to separate an intra-
enhance proliferation. cellular action from that induced by its extracellular ac-
8. One of the actions of the soluble sphingosine 1-phos- tion. An intracellular action of S1P has been proposed for
phate (S1P) is to diffuse out of the cell passing through phagosome maturation, where it releases the Ca 2 + neces-
the ABCC1 transporter, which is a family member of sary to activate the formation of PtdIns3P on endosomes
the ATP-binding cassette (ABC) transporters (Module (Module 4: Figure phagosome maturation). One of the
3: Table ABC transporters). The extracellular S1P then problems with trying to establish such an intracellular ac-
activates EDG receptors, which belong to the family tion for S1P is that it could also mobilize internal Ca 2 +
of G protein-coupled receptors (GPCRs) (Module 1: by acting through the EDG receptors to generate InsP 3 .
Table G protein-coupled receptors) that are capable of However, there are indications that S1P can act directly to
relaying information down a number of signalling path- release Ca 2 + from an internal store. Unlike InsP 3 , how-
ways. ever, release occurs without the appearance of elementary
9. These signalling pathways control cellular pro- events. One of the difficulties with this hypothesis is that
cesses, such as cell survival, proliferation and anti- the channel on the endoplasmic reticulum (ER) that is
inflammatory responses, which are opposite to those opened by S1P remains to be identified. An earlier pro-
controlled by ceramide. posal that S1P might act through Scamper has not been
substantiated. Another suggestion is that S1P functions as
This sphingomyelin signalling pathway has been implic- the Ca 2 + influx factor (CIF) that is proposed to link store
ated in a number of cellular processes: depletion to Ca 2 + entry. Another proposed action of S1P is
to activate the extracellular-signal-regulated kinase (ERK)
• S1P has been proposed to release the Ca 2 + necessary to cascade to promote proliferation. Overexpression of the
activate the formation of PtdIns3P on endosomes during SPHK can induce tumour formation. Therefore the pre-
phagosome maturation (Module 4: Figure phagosome cise role of S1P and its relationship to ER signalling require
maturation). further clarification.
• S1P appears to contribute to the CD28 co-stimulatory
pathway during T cell activation (Module 9: Figure T Ceramide
cell signalling map). This is an enigmatic messenger in that it has been linked
• S1P contributes to the communication between en- to both proliferation and apoptosis, depending very much
dothelial cells and pericytes during angiogenesis (see on the background activity of other messenger systems.
Step 6 in Module 9: Figure angiogenesis signalling). In keeping with its different functions, ceramide can ac-
tivate a number of signalling components such as the
ceramide-activated protein kinase (CAPK), protein kinase
Sphingosine 1-phosphate (S1P) Cζ (PKCζ) and ceramide-activated protein phosphatases
The key enzyme in the formation of sphingosine 1- (CAPP), such as PP1 and PP2A. Some of these ceramide
phosphate (S1P) is sphingosine kinase (SPHK).The mes- targets enable it to interact with other signalling systems
senger function of S1P is complicated by the fact that it such as the c-Jun N-terminal kinase (JNK) and mitochon-
may have both intra- and extra-cellular actions. drial systems. With regard to the latter, ceramide may ac-
S1P can exert its extracellular action either in an tivate mitochondrial reactive oxygen species (ROS) form-
autocrine mode (activate the same cell from which it is ation through ceramide-activated protein kinase (CAPK).
released) (see Step 8 in Module 2: Figure sphingomyelin It is important to stress that apoptosis can occur without
signalling)ora paracrine mode (diffuse away to activate the need for ceramide. However, there is overwhelming
neighbouring cells). This extracellular action is mediated evidence that the formation of ceramide can strongly tip
by endothelial differentiation gene (EDG) receptors, so- the balance in favour of apoptosis. It contributes to this
called because they were first described in human um- activation of the cell death programme by activating the
bilical vein endothelial cells induced to differentiate by intrinsic pathway at the level of the mitochondria (Module
phorbol esters. There is a family of these EDG receptors 11: Figure apoptosis). One way of interacting with the mi-
that are all G protein-coupled receptors (GPCRs) capable tochondria depends on its activation of the JNK pathway,
of activating most of the conventional signalling pathways which is known to induce apoptosis (Module 2: Figure
(Module 1: Table G protein-coupled receptors). The EDG JNK signalling). Ceramide can also activate cathepsin D,
1, 3, 5, 6 and 8 receptors mediate the action of S1P, whereas which converts Bid into tBid, which is one of the pro-
the EDG 2, 4 and 7 receptors appear to respond to lyso- apoptotic members of the Bcl-2 superfamily.
phosphatidic acid (LPA), a related lysolipid. The EDG re-
ceptors that function to induce a mobilization of internal Sphingomyelinases (SMases)
Ca 2 + act by stimulating the formation of inositol 1,4,5- Sphingomyelinases (SMases) exist in different isoforms
trisphosphate (InsP 3 ). One function of the EDG receptors that can be distinguished by their pH optima: acidic, neut-
is to regulate cell motility and directional migration. An ral or alkaline. The last is found in bile and plays a role in di-
example of the latter is preosteoclast chemotaxis where S1P gestion. Sphingomyelin signalling seems to depend on the
directs preosteoclasts form the bone marrow back into the acidic and neutral isoforms (Module 2: Figure sphingomy-
blood (Module 8: Figure preosteoclast chemotaxis). elin signalling). The neutral SMase functions to generate

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