It summarizes notch signalling pathway, and types of notch ligand and notch receptors

1. ASSIGNMENT # 03
NOTCH SIGNALLING PATHWAY
Submitted To: Dr. Jamshaid Hussain
Submitted By: Nazal Gul (SP19-BTY-007)
Date of Submission: 2nd June, 2022

2. Contents:
 Introduction to Notch Signalling
 Notch Receptors
 Ligands
 Notch Signalling Pathway
 Functions of Notch Signalling Pathway
 Notch Pathway and Diseases

3. Introduction
 Notch Signalling is an “Evolutionary Conserved Signalling Pathway”.
 Important in development and homeostasis.
 It regulates cellular proliferation, differentiation and apoptosis.
 It is unique from other signalling pathways due to its ligands.
 Signalling is restricted to neighboring cells.
 This pathway is associated with tissue growth and cancer.
 Also, it is involved in cell death and tumor suppression.

4. Discovery
 In 1914, John S. Dexter noticed the appearance of a notch in the wings of
the fruit fly Drosophila melanogaster.
 The alleles of the gene were identified in 1917 by Thomas Hunt Morgan.
 Its molecular analysis and sequencing was done in the 1980s by Spyros
Artavanis-Tsakonas and Michael W. Young.

5. Notch Receptors
 Notch Signalling is the most widely used intercellular communication pathway.
 There are 4 NOTCH Receptors found in mammals.
 These are: NOTCH1, NOTCH2, NOTCH3 AND NOTCH4.
 This receptor is a single-pass transmembrane receptor protein.
 It is a heterodimer of 2 sub-units.
 The first subunit is an extracellular segment with EGF repeats.
 The second subunit consists of;
- A short extracellular domain
- A transmembrane domain
- And an intracellular domain.

6. STRUCTURE OF NOTCH RECEPTORS
Source:
https://www.researchgate.net/publication/308993039_Targeting_Notch_as_a_Therapeutic_Ap
proach_for_Human_Malignancies

7. Notch Ligands
 Notch ligands are type I transmembrane proteins.
 The ligands of the Notch receptors are characterized into 2 families;
 1. Jagged Protein Family (includes JAG 1 and JAG 2)
 2. Delta-like Protein Family (includes DLL1, DLL3, and DLL4)
 Ligand Extracellular domains are highly conserved in evolution.
 They are essential for ligand-receptor binding to activate Notch signaling.
 Intracellular domain of Notch ligands is short, only contains 70 amino acid
residues.

8. STRUCTURE OF NOTCH LIGANDS
Source:
https://www.creativebiomart.net/resource/signal-pathway-notch-signal-pathway-387.htm

9. NOTCH SIGNALLING
 Notch Signalling Pathway involves inter-cellular signalling interactions.
 Two cells are involved: sending cell and receiving cell
 Sending has more ligands than Notch receptors.
 Receiving cell has more Notch receptors than ligands.
 The ligand-receptor crosstalk controls cell fate decisions through which neuronal,
cardiac, immune, and endocrine development are regulated.
 Binding of the Delta/Jagged ligand on one cell to the Notch receptor on another cell
results in two Proteolytic Cleavages of the receptor.
 The ADAM10 or TACE metalloprotease catalyzes the S2 cleavage.

10. Source:
https://www.creativebiomart.net/resource/signal-pathway-notch-signal-pathway-387.htm
NOTCH SIGNALLING PATHWAY

11. Continued…
 This generates a substrate for S3 cleavage by the γ-secretase complex.
 This proteolytic processing mediates release of the Notch intracellular domain
(NICD).
 NICD enters the nucleus and interacts with the DNA-binding CSL (CBF1, Su(H) and
LAG-1) protein.
 The co-activator Mastermind (Mam) and other transcription factors are recruited to
the CSL complex.
 At the same time, co-repressors (Co-R) are released.
 The co-activators carry out the transcription of target genes e:g P21, CyclinD1 and
cMYC.
 These are crucial for cell division and cell cycle progression.
 This leads to cellular proliferation.

12. Source:
https://www.creativebiomart.net/resource/signal-pathway-notch-signal-pathway-387.htm
NOTCH SIGNALLING PATHWAY

13. Functions of Notch Signal Pathway
 Neuronal function and development
 Stabilization of arterial endothelial fate and angiogenesis
 Regulation of crucial cell communication events
 Cardiac valve homeostasis
 Timely cell lineage specification of both endocrine and exocrine pancreas
 Influencing of binary fate decisions of cells that must choose between the secretory
and absorptive lineages in the gut
 Expansion of the hematopoietic stem cell compartment during bone development

14. Continued…
 T cell lineage commitment from common lymphoid precursor
 Regulation of cell-fate decision in mammary glands at several distinct development
stages
 Regulation of the mitotic/meiotic decision in the C. elegans germline

15. Notch Signal Pathway and Diseases
 The abnormality of this regulatory signalling mechanism often leads to congenital
genetic diseases.
 It has been confirmed that the mutations of related genes in the Notch signaling
pathway are associated with genetic diseases such as CADASIL, Aligile's syndrome
and hypogastric hypoplasia.
 Delta 3 gene mutations can cause autosomal recessive diseases.
 A study found that Notch signaling disorders associated with certain cardiovascular
diseases.
 Animal model experiments show that it may affect the cardiovascular system from
four aspects, including vascular remodeling, vascular stability, choice of
arteriovenous and heart development.

16. Continued…
 Recent studies have found that the cleavage of amyloid precursor protein and Notch
receptor are all dependent on γ-secretase.
 So it is speculated that Notch signaling pathway may have some connection with
the occurrence and development of Alzheimer's disease.

17. Conclusion
 Notch signal is in a complex multi-dimensional regulatory network that provides a basis
for multiple functions in development.
 For example, endocytic transport of Notch receptors and ligands plays an important role
in the activation of Notch signaling.
 Ubiquitin-mediated protein degradation is crucial for preventing the continuous
activation of Notch signaling, yet its regulatory mechanism remains to be elucidated.
 The main task of future research is to unveil the mechanisms of the complex regulatory
networks of Notch signaling.
 Also, recognizing the basis for the diversity of functions of Notch signaling that will allow
us to design more specific approaches.
 And developing treatment programs to specific pathologies resulting from aberrant Notch
signaling.

18. References
 https://www.researchgate.net/publication/308993039_Targeting_Notch_as_a_Therape
utic_Approach_for_Human_Malignancies
 https://www.sciencedirect.com/science/article/abs/pii/B9780123852335000076
 https://www.frontiersin.org/articles/10.3389/fphys.2020.00929/full
 Yamamoto S, Schulze KL, Bellen HJ. Introduction to Notch signaling. Methods Mol
Biol. 2014;1187:1-14. doi: 10.1007/978-1-4939-1139-4_1. PMID: 25053477.