Notch signaling pathway

breif introduction of notch signaling pathway.

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. 2

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 3

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 4

5. Involved in 5 Multiple tissues Multiple development process Differentiation Proliferation Movement Apoptosis Cell fate choices

6. The development logic of notch : CELL TO CELL SIGNALING 6 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 . 7

8. 8

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. 9

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 . 10

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. 11

12. 12

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 13

14. 14 THANKS A LOT