The Notch signaling pathway relies on regulated proteolysis and involves lateral inhibition. Upon binding of the Delta ligand to the Notch receptor on a signaling cell, the Notch receptor undergoes a series of cleavages that releases its intracellular domain. This domain then translocates to the nucleus and influences gene expression. Precise proteolytic cleavage of the Notch receptor is required for the pathway to function properly in numerous developmental processes. Aberrations in the Notch pathway can lead to various disorders and cancers.

1. Notch signaling Pathway
And associated
Syndromes/disorders
Signaling Pathways That Depend on Regulated Proteolysis

2. Signaling Pathways That Depend on Regulated
Proteolysis
The need for intercellular signaling is never greater than
during animal development.
 Each cell in the embryo has to be guided along one
developmental pathway or another according to its history, its
position, and the character of its neighbors.
At each step in the pathway, it must exchange signals with its
neighbors to coordinate its behavior with theirs.
Ensuring the coordination which leads to the correct number
on a tissue and organ.
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3.  Most of the signaling pathways already discussed are widely used for these purposes.
 But there are also others that relay signals in other ways from cell-surface receptors to the
interior of the cell.
 These additional signaling pathways all depend, in part at least, on regulated proteolysis.
 Following are the pathways that are dependent on regulated proteolysis
 the pathway activated by secreted Wnt proteins
 the pathway activated by secreted Hedgehog proteins
 the pathway mediated by the receptor protein Notch
 the pathway that depends on activation of the latent gene regulatory protein NF-κB.
 Most of these pathways were discovered in drosophila
 Highly conserved in Evolution
 Used over and over again during development
 Have crucial role in many developmental processes
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4. Signaling through Notch receptor
pathway
HISTORY
 Signalling through notch receptor pathway may be the most
widely used signaling pathway in animal development.
• Notch protein discovered in Fruit fly by 1917 by T.H Morgan.
• Involved in epithelial differentiation and proliferation
• Also involved in human development
• D F pulson 1985 was first one to link genes with development
• Spyros Artavanis-Tsakonas worked on drosophila and discovered
this pathway
• Phenotype of notch became more important
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5. Involved in5
• Multiple tissues
• Multiple development process • Differentiation
• Proliferation
• Movement
• Apoptosis
• Cell fate choices

6. The development logic of notch : CELL TO
CELL SIGNALING
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Example: Lateral inhibition
• Production of nerve cell in drosophila
• This nerve cell usualy arise as an
isolating signaling cell with an epithilial
sheet of precursor cell
• When it commits to become a nerve
cell ,It sends signals to its imidiate
neibours not to do the same
• Hence the inhibited cells develop into
Epithilial cells.

7. Notch signaling Pathway
 Lateral inhibition depends upon a contact dependent signaling and that’s activated by
the
 Transmembrane signaling protein called as “Delta” or “Serate(In fruitfly)
 Ligand : DELTA PROTEIN (comes from the signaling molecule)
 Receptor: Notch protein.
 Both Notch and Delta proteins are glycoproteins means both of them are membrane
bounded ligand and receptor.
 Initially cell represent equivalent level of both ligand and receptor.
 Their expression depends on many machanisms repressing of and expressing other.
 Both Notch and Delta are single-pass transmembrane proteins, and both require
proteolytic processing to function.
 Although it is still unclear why Delta has to be cleaved.
 the cleavage of Notch is central to how Notch activation alters gene expression in
the nucleus.
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9. The cleavage of notch receptor and
signaling
 Notch gene encodes a receptor within a sigle transmembrane domain.
 Initially notch is synthsized as a single protein.
 The Notch receptor undergoes three proteolytic cleavages.
1_The cleavage of notch receptor into Golgi apparatus(S1 clevage)
 As part of its normal biosynthesis, a protease called furin acts in the Golgi
apparatus to cleave the newly synthesized Notch protein in its future
extracellular domain.
 This cleavage converts Notch into a heterodimer, which is then
transported to the cell surface as the mature receptor.
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10. The cleavage of notch receptor and
signaling
 The Mature receptor now is consisting of three domains ( NECB,TM,NICD)
 Signaling starts when notch interact with the ligand
 Now this interaction further triggers two cleavages.
 Cleavage after binding to delta (S2 Clevage)
 The binding of delta to notch induces cleavage in the extra cellular
domain(NECD) mediated by an extracellular protease.
 Final Cleavage (S3 Clevage)
 Final cleavage quicly follows cutting free the cytoplasmic tail of activated
receptor.
 The cleavage of the Notch tail occurs very close to the plasma membrane,
just within the transmembrane segment,By Secretase.
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11. Translocation of the Nucleus
 The free intracellular fragment then gets translocated to the
nucleus
 Where it binds to the transcription regulator (CSL) ,resulting in the
displacement of co repressor previously bound to CSL.
 Co-Activator then induces the expression related proteins.
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13. Notch pathway and Disorders
 There are different types of Notch receptors
 Notch1, Notch2, Notch3, Notch4
 Many kind of mutation, stress,
 Somatic mutations in certain Notch pathway genes are increasingly
being shown to contribute to various cancerous conditions.
 Shizopherenia
 Algile
 Casdail
 Brain tumors
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