Introduction to Delta-Notch Signalling

The Delta-Notch signalling pathway is a highly conserved cellular signaling mechanism that is essential for embrionic development in a wide variety of organisms.

Notch genes encode for transmembrane protiens, Delta is an example of one of the ligands that bind to the extracellular domain of the Notch receptor in Drosophila. Delta is a single-pass transmembrane protein ligand that is membrane bound. The subsequent signaling from the binding of Delta to Notch results in proteolytic cleavage which then allows for the intracellular portion of Notch to go on and make changes to gene expression in the nucleus. 

The following diagram depicts the signalling pathway:

(Image courtesey of Humpath.com. Humpath.com: Disclaimer)

Cleavage and Processing of the Notch receptor: 

There are 3 cleavages required in the Delta-Notch signalling pathway, each requires a different enzyme: 

S1 Cleavage: FURIN enzyme. Furin cleaves the Notch protein as it leaves the Golgi Apparatus, producing a heterodimer which incorporates into the membrane where it is inactive.

S2 Cleavage: TACE enzyme. Tace cleaves the Notch protein when Delta has bound, therefore this cleavage is a ligand dependant step. 

S3 Cleavage: PRESENILIN enzyme. Presinilin cleaves Notch after ligand binding. This cleavage occurs in the transmembrane domain, producing Notch(intra) which translocates to the nucleus. 

(Image again shows cleavage process of Notch as well as action of Notch in nucleus. Image courtesy of: BMC)

Once inside the nucleus:

Notch(intra) acts on the CSL/CBF1 transcription factor complex.

In the absence of Notch in the nucleus, this complex is bound to SMRT & SKIP proteins forming a HDAC (Histone deacetylase complex) which inactivates Notch gene transcription.

Notch has RAM & ANK regions which, on entry to the nucleus, displace SMRT & SKIP respectively and therefore act to activate gene transcription.

 Other Notch domains include:

•  NLS sequence required for its nuclear localization
•  Activation doman.

Notch signalling determines cell fate of surounding cells by the process of lateral inhibition in both vertbrates and invertebrates. Different Notch activation results in different biological alterations in gene expression. For example in human adult tissue, activation of Notch1 corresponds to differentiation of T-cells and self-renewal, which path is undertaken is dependent on other environmental factors too.