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NOTCH SIGNALLING
INTRODUCTION
• Notch is a single transmembrane protein located on the
cell surface with transmembrane ligands.
• The signalling event is triggered by cell-cell contact
which is essential for this event.
• Notch plays a dual role as a transmembrane receptor
and a transcription factor.
• The notch ligands are also single-pass transmembrane
proteins and are members of the DSL
(Delta/Serrate/LAG-2) family of proteins.
Domains of notch protein
• Notch protein has 3 domains
1. Extracellular domain
2. Transmembrane domain
3. Intracellular domain
• The notch extracellular domain is composed
primarily of small cystine-rich motifs
called EGF-like repeats.
Signal sending
cell
Signal receiving
cell
MAML=Master like mind
NOTCH signaling pathway
1. In the golgi apparatus the Notch receptor
undergoes proteolytic processing, which is S1
cleavage mediated by Furin proteases.
2. The receptor is transported to the cell surface
membrane.
3. The extracellular domain of the Notch
receptor (Notch-ECD) in the signalling cell
binds with the Notch ligands (Delta, Jagged,
Serrate) expressed by the adjacent cell.
NOTCH signaling pathway
4. This induces the second proteolytic step, S2 cleavage
by ADAM family metalloproteases ADAM10. This
releases the extracellular portion of notch (NECD), which
continues to interact with the ligand. The ligand plus the
notch extracellular domain is then endocytosed by the
ligand-expressing cell.
5. This is followed by the release of the Notch
intracellular domain (Notch-ICD) with a tethered
membrane. This is now a substrate for the gamma
secretase enzyme complex, which cleaves the Notch-ICD
from the membrane by S3.
NOTCH signaling pathway
6. The resulting active Notch-ICD translocates to
the nucleus and interacts with the CSL protein.
7. In the absence of Notch-ICD, the CSL is
bound to co-repressor. Binding of Notch-ICD
with CSL results in the formation of an active
complex with MAML and other co-activators
and leads to the transcription of Notch targets.
Lateral inhibition
• The receptor is normally triggered via direct cell-to-cell
contact, in which the transmembrane proteins of the cells in
direct contact form the ligands that bind the notch receptor.
• The Notch binding allows groups of cells to organize
themselves such that, if one cell expresses a given trait, this
may be switched off in neighbouring cells by the
intercellular notch signal. In this way, groups of cells
influence one another to make large structures.
• Thus, lateral inhibition mechanisms are key to Notch
signaling.
NOTCH signaling |Lateral inhibition

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NOTCH signaling |Lateral inhibition

  • 2. INTRODUCTION • Notch is a single transmembrane protein located on the cell surface with transmembrane ligands. • The signalling event is triggered by cell-cell contact which is essential for this event. • Notch plays a dual role as a transmembrane receptor and a transcription factor. • The notch ligands are also single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins.
  • 3. Domains of notch protein • Notch protein has 3 domains 1. Extracellular domain 2. Transmembrane domain 3. Intracellular domain • The notch extracellular domain is composed primarily of small cystine-rich motifs called EGF-like repeats.
  • 4.
  • 5.
  • 6.
  • 7.
  • 8.
  • 10. NOTCH signaling pathway 1. In the golgi apparatus the Notch receptor undergoes proteolytic processing, which is S1 cleavage mediated by Furin proteases. 2. The receptor is transported to the cell surface membrane. 3. The extracellular domain of the Notch receptor (Notch-ECD) in the signalling cell binds with the Notch ligands (Delta, Jagged, Serrate) expressed by the adjacent cell.
  • 11. NOTCH signaling pathway 4. This induces the second proteolytic step, S2 cleavage by ADAM family metalloproteases ADAM10. This releases the extracellular portion of notch (NECD), which continues to interact with the ligand. The ligand plus the notch extracellular domain is then endocytosed by the ligand-expressing cell. 5. This is followed by the release of the Notch intracellular domain (Notch-ICD) with a tethered membrane. This is now a substrate for the gamma secretase enzyme complex, which cleaves the Notch-ICD from the membrane by S3.
  • 12. NOTCH signaling pathway 6. The resulting active Notch-ICD translocates to the nucleus and interacts with the CSL protein. 7. In the absence of Notch-ICD, the CSL is bound to co-repressor. Binding of Notch-ICD with CSL results in the formation of an active complex with MAML and other co-activators and leads to the transcription of Notch targets.
  • 13. Lateral inhibition • The receptor is normally triggered via direct cell-to-cell contact, in which the transmembrane proteins of the cells in direct contact form the ligands that bind the notch receptor. • The Notch binding allows groups of cells to organize themselves such that, if one cell expresses a given trait, this may be switched off in neighbouring cells by the intercellular notch signal. In this way, groups of cells influence one another to make large structures. • Thus, lateral inhibition mechanisms are key to Notch signaling.