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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 119

Delta and this is an important aspect of the modulation of Notch
Delta is a transmembrane protein that functions as one signalling (Module 2: Figure Notch modulation).
of the stimuli that activate the Notch receptor (Module
2: Table Notch signalling components). The extracellu-
lar domain is made up of EGF-like repeats and there is Endoplasmic reticulum (ER) stress
an N-terminal DSL (Delta, Serrate and LAG-2) domain signalling
that interacts with the Notch receptor (Module 2: Fig- The endoplasmic reticulum (ER) has sophisticated stress
ure Notch signalling). In order for Delta to function as a signalling pathways that enable it to adapt to a whole host
stimulus, it has to undergo a maturation process, which of stress factors mainly concerned with the way in which
depends upon its passage through the endosome (Module proteins are synthesized and packaged. Maintenance of
2: Figure Notch modulation). This trafficking through the a constant level of Ca 2 + within the lumen of the ER
endosomal compartment determines the amount of Delta is essential for the post-translational processing, folding
in the membrane and this is an important aspect of the and export of proteins. This protein processing is carried
modulation of Notch signalling.The expression of Delta- out by a number of Ca 2 + -sensitive chaperones such as
1 is increased on the surface of myofibres during muscle 78 kDa glucose-regulatory protein (GRP78) [also known
damage and this activates the Notch signalling pathway as immunoglobulin heavy-chain-binding protein (BiP)],
to stimulate the proliferation of satellite cells (Module 8: GRP94 (endoplasmin) and calnexin. GRP78 may function
Figure Satellite cell activation). as a modulator of the InsP 3 receptor by regulating how
this release channel is assembled (Module 3: Figure InsP 3 R
Jagged regulation).
Jagged is a transmembrane protein that functions as a one Any decline in the luminal level of Ca 2 + results in the
of the stimuli that activate the Notch receptor (Module accumulation of misfolded proteins and the activation of
2: Table Notch signalling components). The extracellular the ER stress signalling pathways (Module 2: Figure ER
domain is made up of a cysteine-rich domain, EGF-like stress signalling):
repeats and there is an N-terminal DSL (Delta, Serrate and
1. Oligomerization and autophosphorylation of PKR
LAG-2) domain that interacts with the Notch receptor.
(protein kinase R)-like ER kinase (PERK) sets off a
In order for Jagged to function as a stimulus, it has to
phosphorylation cascade that culminates in the phos-
undergo a maturation process, which depends upon its
phorylation and inactivation of the translation euka-
passage through the endosome (Module 2: Figure Notch
modulation). This trafficking through the endosomal com- ryotic initiation factor eIF-2α, resulting in protein syn-
thesis being switched off.
partment determines the amount of Delta in the membrane 2. Oligomerization and autophosphorylation of IRE1 ini-
and this is an important aspect of the modulation of Notch tiates one of the transcriptional signalling pathways re-
signalling.
sponsible for the up-regulation of the various chaper-
ones.
Notch 3. Another of the transcriptional pathways depends
Notch is a transmembrane protein that functions as the upon the activation of the ER membrane-bound
receptor for the Notch signalling pathway by respond- activating transcription factor 6 (ATF6),which is
ing to stimuli such as Delta and Jagged (Module 2: Figure released from the ER to enter the nucleus, where
Notch signalling). The large extracellular domain of Notch it interacts with the ER stress-response element
is made up of a variable number (29--36) of EGF-like re-
of the C/EBP (CCAAT/enhancer-binding protein)-
peats and a Lin21/Notch repeat region. EGF-repeats 11
homologous protein 10 (CHOP) gene.
and 12 (red bar) on Notch provides the binding site that in-
4. The various chaperones are then expressed within the
teracts with the N-terminal DSL (Delta, Serrate and LAG-
ER, where they participate in protein folding.
2) domain on Delta and Jagged. The cytoplasmic domain
5. One of the genes activated during the stress response
has a series of six ankyrin repeats and a terminal PEST
is CHOP, which acts as a transcription factor and can
domain.
contribute to apoptosis.
Notch undergoes a number of post-translational modi-
6. Caspase 12, which is associated with the ER membrane,
fications as it moves through the endoplasmic reticulum
is also activated and contributes to ER stress-induced
(ER) and the Golgi. While in the ER, certain sites on the
apoptosis.
EGF repeats are fucosylated by the chaperone O-fut. After
7. An excessive accumulation of proteins within the ER
the addition of these fucose groups, further extension of
results in the activation of the transcription factor
the carbohydrate chains is carried out by the Fringe family
nuclear factor κB(NF-κB), which acts to increase the
(Module 2: Table Notch signalling components). The de- production of interferons and cytokines, so contribut-
gree of glycosylation can markedly influence the affinity ing to an inflammatory response.
of the Notch receptor for its ligands. The last modification,
which occurs in the Golgi, is the cleavage of the molecule These stress pathways are then responsible for switching
at site 1 (S1) by the protease; the heterodimeric receptor is off ongoing protein synthesis, for up-regulating the pro-
then inserted into the membrane. duction of new chaperones, for inducing apoptosis and for
Trafficking of Notch through the endosomal compart- activating inflammatory responses. The degree to which
ment determines the amount of receptor in the membrane these different responses are activated depends upon the

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