Page 116 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 116

Module 2: Figure Notch signalling

Endosome
Delta
Jagged
1
2
S2
Notch 3
-secretase
S3 Proteasome
6 Ankyrin
repeats ADAM 4 NICD
PEST
Ub Ub UbUb
P
5 8 9
NICD SEL-10
CDK-8
P
Acetylation
p300 MAM Notch target genes HES1
SKIP HES2
CSL 7
HES7
HEY1
Gene repression 10 6 Gene activation HEY2
HEYL
ESR
Deacetylation HDAC NRARP
SHARP X
SMRT
CSL
Notch signalling pathway.
One of the stimuli for the Notch signalling pathway is Jagged, which is located on the surface of the communicating cell. The receptor for Jagged is
Notch, which is located on the surface of the receiving cell. When Jagged interacts with Notch (Step 1), it triggers a series of steps that result in the
proteolytic release of the Notch intracellular domain (NICD), which then enters the nucleus to activate transcription of Notch target genes. See the text
for details of this sequence of events.

signal transduction process itself, whereas others play a 5. NICD released from the membrane diffuses into the
role in the modulation of Notch signalling,which regu- nucleus and binds to CSL(CBF-1, Suppressor of Hair-
lates the expression of the stimuli (Delta and Jagged)and less, Lag-1).
the Notch receptor at the cell surface. The operation of 6. CSL normally acts to repress Notch target genes.
the Notch signalling pathway depends upon the following Repression is enhanced by CSL providing a frame-
steps (Module 2: Figure Notch signalling): work to recruit co-repressors such as SMRT, SHARP,
SKIP and CIR. This repression complex also recruits
1. Delta or Jagged located on one cell interacts with histone deacetylase (HDAC) that deacetylates chro-
the Notch receptor on a neighbouring cell. The N- matin further shutting down transcriptional activity.
terminal DSL (Delta, Serrate and LAG-2) domain When NICD binds to CSL, the repression complex is
(yellow bar) on Delta/Jagged binds to the EGF- disassembled and this paves the way for the assembly
repeats 11 and 12 (red bar) on Notch. By itself, this of an activation complex. An important part of the
interaction with Notch seems to have little effect and complex is the co-activator Mastermind (MAM) and
only initiates the signal transduction sequence as a the histone acetyl transferase p300. The latter is re-
result of Delta/Jagged physically pulling on Notch. sponsible for protein acetylation of histones to open
2. The endocytosis of Delta/Jagged seems to be a crit- up the chromatin to facilitate gene transcription.
ical step for receptor activation. As Delta/Jagged are 7. Gene activation results in an increase in the transcrip-
drawn into the endosome, they pull on Notch, which tion of Notch target genes. Some of these such as the
undergoes a conformational change to expose site-2 hairy and enhancer of split (HES) family encode tran-
(S2). scriptional repressors responsible for suppressing the
3. S2 is cleaved by ADAM proteases such as ADAM-10 expression of tissue specific proteins, which accounts
and ADAM-17 (Module 1: Table ADAMs proteases). for the ability of the Notch signalling pathway to in-
The external domain is shed leaving behind a short hibit differentiation.
transmembrane region and the intracellular domain, 8. The inactivation of target gene transcription begins
which then becomes a substrate for γ-secretase. when NICD is phosphorylated in the N-terminal
4. The γ-secretase complex is an enzyme complex made PEST domain by kinases such as cyclin-dependent
up of presenilin, nicastrin, PEN2 and APH1 that kinase-8 (CDK-8).
cleaves the S3 site to release the Notch intracellular 9. The phosphorylated NICD becomes a substrate for
domain (NICD). The activity of γ-secretase may be nuclear ubiquitin ligases such as SEL-10 and is then
inhibited by Crumbs, which is an apical polarity pro- exported to the cytoplasm where it is degraded by the
tein. proteasome.

C 2012 Portland Press Limited www.cellsignallingbiology.org