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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 97

Module 2: Figure sphingolipid metabolism

Sphingomyelin Ceramide Sphingosine Sphingosine-1-PO 4
(SM) (Cer) (Sph) (S1P)
30,000 3,000 100 1

O C HO C O C HO C C OH C OH
H H
N C N C N C N C
H H
C C C C
SMase CDase SPHK
O OH OH O
O P O O P OH
O O
C
C
CH 3 N CH 3
CH 3

Sphingolipid metabolism.
The sphingomyelin signalling pathway depends on the conversion of sphingomyelin (SM) into a series of bioactive lipids capable of activating
various signalling mechanisms as described in Module 2: Figure sphingomyelin signalling. The numbers represent the relative cellular levels of these
sphingolipids. SMase, sphingomyelinase; CDase, ceramidase; SPHK, sphingosine kinase. Information for this Figure was taken from Hannun and
Obeid (2008).

opposed, such as proliferation and apoptosis. A clue to by dihydroceramide synthase (CerS). Finally, a desat-
this complexity lies in the fact that the pathway can spawn urase converts dhCer into ceramide (Cer). Mutations
a number of messengers, and the action of these is very in serine palmitoyl transferase (SPT) are responsible for
dependent on the current state of the cell, especially with type I hereditary sensory and autonomic neuropathies
regard to what other signalling pathways are active. (HSAN).
2. The ceramide formed at the ER is then transported
to the Golgi by a ceramide transfer protein (CERT).
Generation and function of ceramide and
sphingosine 1-phosphate (S1P) A sphingomyelin synthase (SMS) located in the Golgi
The generation of ceramide and sphingosine 1-phosphate converts ceramide into sphingomyelin (SM), which is
(S1P), which are the two main bioactive ’messenger’ lip- transferred to the membrane through a vesicle transport
ids of the shingomyelin signalling pathway, begins with mechanism.
the hydrolysis of sphingomyelin (SM) by various sphin- 3. The hydrolysis of SM in the plasma membrane is activ-
gomyelinases (SMases) to form ceramide (Module 2: Fig- ated by receptors sensitive to stimuli such as tumour
ure sphingolipid metabolism). A ceramidase (CDase) then necrosis factor α (TNFα), interleukin 1, CD28 and
cleaves off one of the fatty acid chains to form sphingosine Fas. The coupling between receptors and the neutral
(Sph), which is then phosphorylated by sphingosine kinase sphingomyelinases (SMases) has been worked out in
(SPHK). As illustrated by the figures in Module 2: Fig- some detail for the TNFα receptor. A factor associated
ure sphingolipid metabolism, the relative cellular levels of with neutral SMase (FAN) functions to couple the en-
these sphingolipids vary enormously. The precursor SM is zyme to the neutral SMase activation domain (NSD)
present at the highest level and this then declines during of the TNFα receptor. These components of the sphin-
the different metabolic transformations. gomyelinase signalling pathway are often highly con-
An important aspect of this sphingomyelin signalling centrated in lipid rafts and caveolae, which represent
pathway is the cellular location and function of these dif- the site where some of the sphingomyelinases function
ferent metabolic steps (Module 2: Figure sphingomyelin to hydrolyse sphingomyelin.
signalling): 4. The activation of neutral SMase at the plasma mem-
brane provides one of the major sources of ceramide
1. Sphingomyelin synthesis is carried out first in the endo- (Cer), which can then be metabolized to other sig-
plasmic reticulum (ER), where ceramide is formed, and nalling sphingolipids (Module 2: Figure sphingolipid
is completed by the Golgi. The first step is carried out metabolism). A ceramidase (CDase) hydrolyses Cer to
by serine palmitoyl transferase (SPT) that combines ser- sphingosine (Sph), which can then be phosphorylated
ine and palmitate to form dihydrosphingosine (dhSph), by sphingosine kinase (SPHK) to form sphingosine
which is then converted into dihydroceramide (dhCer) 1-phosphate (S1P). Since the latter is soluble, it leaves

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