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Fig. 3. Structure and functional organization of Notch signalling. Notch and
its ligands (members of the DSL family) are transmembrane proteins. (A)
In the absence of ligand, the full-length Notch protein is present at the cell
surface as a heterodimer of the extracellular (ECN) and the
transmembrane-intracellular domains. (B) (a) Binding of a Notch ligand
(Serrate/Jagged/Delta) to specific EGF-like repeats (blue) triggers (b) a
proteolytic cleavage, S2, in the extracellular juxtamembrane region (grey) of
Notch by members of the ADAM tumour necrosis factor converting enzyme (TACE)
proteases. This event primes (c) a second ligand-independent cleavage, S3,
within the transmembrane domain (purple) of Notch, which is catalysed by the
Presenilin-
-secretase complex. As a result of S3 cleavage, (d) the
intracellular domain of Notch (NICD) enters the nucleus, where it (e)
interacts with CSL, displaces co-repressors and through Mastermind (MAML)
recruits co-activators to (f) promote the transcription of target genes. For
further details, see text and published literature
(Bray, 2006;
Ehebauer et al., 2006;
Kopan, 2002;
Le Borgne, 2006). ADAM, a
disintegrin and metalloprotease; CBP, CREB binding protein (also known as
Crebbp); CSL, CBF/Suppressor of Hairless/LAG-1; DSL, Delta/Serrate/LAG-2; ECN,
Extracellular Notch; Pol II, RNA polymerase II; TACE, TNF
-converting
enzyme.
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