Page 100 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 100

ceramide in response to the activation of receptors sensit- subunit. In the case of CAPP, ceramide acts to stimulate
ive to stimuli such as tumour necrosis factor α (TNFα) and phosphatase activity by binding to one of the regulatory
interleukin 1 (see Step 3 in Module 2: Figure sphingomy- B subunits. The ability of ceramide to inhibit growth is
elin signalling). The acidic form was originally identified probably mediated through PP2A.
in lysosomes where it generates ceramide in response to
stress stimuli (see Step 5). There also are indications that Scamper
the acidic SMase may act on sphingomyelin located in the A sphingolipid Ca 2 + -release-mediating protein of the en-
outer leaflet. The acidic SMase is a component of lipid rafts doplasmic reticulum (ER) (Scamper) was originally pro-
and caveolae, which are microdomains of the plasma mem- posed to be the Ca 2 + channel on the ER that responds
brane containing high levels of the precursor sphingomy- to signals from the sphingomyelin signalling pathway,
elin. It is this acidic isoform that is defective in patients but more recent studies have shown that it has a single
with Niemann-Pick disease. membrane-spanning segment that seems to remodel the
actin cytoskeleton.
Ceramide-activated protein kinase (CAPK)
Ceramide-activated protein kinase (CAPK) is a Janus kinase (JAK)/signal transducer
membrane-bound proline-directed protein kinase and activator of transcription (STAT)
that acts by phosphorylating Raf-1, thereby enabling signalling pathway
ceramide to plug into the mitogen-activated protein kinase The Janus kinase (JAK) and the signal transducer and ac-
(MAPK) cascade and could account for those cases where tivator of transcription (STAT) function in the JAK/STAT
ceramide promotes both inflammation and proliferation.
signalling pathway provides a mechanism for rapidly ac-
tivating gene transcription in response to a large num-
Sphingosine kinase (SPHK) ber (>35) of external ligands. This signalling pathway is
Sphingosine kinase (SPHK) appears as two isoforms mainly activated by cytokines such as interferon, but is
(SPHK1 and SPHK2), which have different tissue dis-
also used by receptor tyrosine kinases [epidermal growth
tributions. SPHK1 is found at high levels in the lung
factor receptor (EGFR), platelet-derived growth factor
and spleen, whereas SPHK2 is expressed mainly in liver
receptor (PDGFR)], non-receptor tyrosine kinases and
and heart. Both have five highly conserved domains, with
G protein-coupled receptors (GPCRs). The Janus kinase
the ATP-binding site and catalytic site located in the C2
(JAK)/signal transducer and activator of transcription
domain. (STAT) structure reveals the major features of these two
The enzyme is both membrane-bound and free in the
cytosol, and there is some uncertainty as to how it is components and how they are linked during the signal
transducer and activator of transcription (STAT) activa-
activated by cell-surface receptors. It seems likely that tion cascade. Cell-surface receptors act by phosphorylat-
it responds to various downstream signals emanating ing the STATs, which are latent transcription factors. Once
from these receptors such as Ca 2 + /calmodulin, diacylgly- phosphorylated, these STATs leave the membrane and
cerol (DAG)/protein kinase C (PKC), cyclic AMP/protein then dimerize before migrating into the nucleus where
kinase A (PKA) or extracellular-signal-regulated kinase they bind to specific DNA-binding elements to activate
1/2 (ERK1/2) (see Step 4 in Module 2: Figure sphingomy- transcription. There is considerable evidence for a Janus
elin signalling). Another activator is oxidized low-density kinase (JAK)/signal transducer and activator of transcrip-
lipoprotein (LDL), which may play a role in cell prolifera- tion (STAT) function in growth and development.
tion. Consistent with the activation by various messenger Mutations in STAT3 have been linked to hyper-IgE syn-
pathways is the fact that SPHK contains consensus se- drome (HIES).
quences for Ca 2 + /calmodulin binding and phosphoryla-
tion sites for PKA, casein kinase II and PKC. Janus kinase (JAK)/signal transducer and
activator of transcription (STAT) structure
Sphingosine 1-phosphate (S1P) phosphatase (SPP) The two major components of the signalling pathway
Mammals have two sphingosine 1-phosphate (S1P) phos- are the Janus kinases (JAKs) and their substrates the sig-
phatases (SPPs). Both SPP1 and SPP2 have eight to ten nal transducers and activators of transcription (STATs)
transmembrane domains that locate the enzymes within (Module 2: Figure JAK and STAT structure). Of the four
the endoplasmic reticulum (ER). SPP-1 is located mainly mammalian JAKs, three are expressed fairly ubiquitously,
in the placenta and kidneys, whereas SPP2 is found in the whereas JAK3 is restricted to natural killer (NK) cells
brain, heart, colon, kidney, small intestine and lung. These and thymocytes, with some expression in vascular smooth
enzymes convert S1P back into ceramide and can diminish muscle cells and endothelium. The main structural com-
survival and promote apoptosis (see Step 6 in Module 2: ponent of the JAKs is the kinase domain that functions to
Figure sphingomyelin signalling). phosphorylate the STATs at a key tyrosine in the region of
residue 700 during the signal transducer and activator of
Ceramide-activated protein phosphatase (CAPP) transcription (STAT) activation cascade.The STATshave
Ceramide-activated protein phosphatase (CAPP) is a a number of functional domains whose three-dimensional
member of the protein phosphatase 2A (PP2A) family of structure reveals how the STAT dimers are formed and
serine/threonine phosphatases that consist of three sub- how they bind to DNA (Module 2: Figure STAT1/DNA
units: A and B are regulatory, whereas C is the catalytic complex).

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