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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 118

Module 2: Figure Notch modulation

Ligand maturation Ub Ub Degredation

3
Ub
2 Ub
Epsin Recycling
1
Neur Mib Ub Ub PtdIns4,5P 2 Ub
Delta
Jagged
8
Notch
NAK
4
Numb
-adaptin Recycling
7
MVB
Receptor maturation
Endosome
Ub
Itch 6
5
Deltex Degredation Ub
Ub
Modulation of Notch signalling.
Trafficking through the endosomal compartment plays an important role in regulating the maturation/activity of the Notch ligands (shown at the top)
and the Notch receptor (shown at the bottom). See text for further details. Mib, Mind bomb; MVB, multivesicular body; Neur, Neutralized; NAK,
Numb-associated kinase; Ub, ubiquitin.

has been identified in both ovarian and medullablastomas. PtdIns4,5P 2 regulation of membrane trafficking and en-
An up-regulation of Notch and a decrease in the inhib- docytosis.
itor Numb has been observed in breast cancer. Mutations 3. The endosome then has two paths: it can move down
in Notch have been linked to T cell acute lymphoblastic the lysosomal path resulting in degradation of Delta and
leukaemia. Jagged. Alternatively, it can recycle back to the plasma
membrane where the ligands are then able to activate
Notch.
Modulation of Notch signalling
The primary mechanism for modulating Notch signalling Different players function in the regulation of Notch
is to adjust the mechanisms responsible for regulating both trafficking as shown in the following steps (Module 2:
ligand (Delta and Jagged) and receptor (Notch) maturation Figure Notch modulation):
(Module 2: Figure Notch modulation). In both cases, the
ligands and the receptor on the cell surface are taken up 4. Entry of Notch into the endosome is dependent on the
into the endosomes and are then either recycled back to the protein Numb, which is a major inhibitor of Notch
cell surface or are degraded. The balance between recycling signalling. The Notch receptor interacts with Numb,
and degradation thus determines their level of membrane which also binds to α-adaptin. The latter is a component
expression and thus sets the sensitivity of the Notch sig- of the adaptor protein-2 (AP2) complex responsible for
nalling pathway. The ubiquitin-proteasome system plays endocytosis. A Numb-associated kinase (NAK) is also
a critical role in regulating the trafficking of these two a component of this complex. The Notch receptors in
signalling components. the endosome have two fates.
The trafficking of Delta and Jagged follows the fol- 5. Some of the Notch receptors are ubiquitinated by
lowing series of events (Module 2: Figure Notch mod- ubiquitin ligases such as Itch (a Hect domain E3 lig-
ulation): ase) and Deltex (a Ring finger E3 ligase).
6. Ubiquitinylated notch receptors are transferred to the
1. The cytoplasmic domain of Delta and Jagged are ubi- multivesicular body (MVB) en route to degradation by
quitinylated by Ring finger E3 ubiquitin ligases such as the lysosome.
Mind bomb (Mib) and Neutralized (Neur). 7. Some of the Notch receptors are recycled back to the
2. Endocytosis of these ubiquitylated proteins is facil- plasma membrane.
itated by the protein epsin that binds to ubiquitin- 8. These Notch receptors on the cell surface are then able
containing cargo proteins. In addition, epsin binds to interact with ligands such as Delta and Jagged to
to both clathrin and to phosphatidylinositol 4,5- initiate the Notch signalling pathway (Module 2: Figure
bisphosphate (PtdIns4,5P 2 ), which functions in the Notch signalling).

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