Figure 2.

NOTCH signaling pathway. Ligand expressed on the surface of the signal-sending cell binds to NOTCH expressed on the surface of the signal-receiving cell and induces sequential cleavages by A-Disintengrin-And-Metalloprotease (ADAM) and γ-secretase, ultimately releasing the NOTCH intracellular domain (NICD) from the membrane. NICD translocates to the nucleus where it mediates the displacement of co-repressors (CoR) and Histone DeAcetylase Complex (HDAC) and directly interacts with RBPJk recruiting co-activators (CoAct), finally inducing target gene transcription. The signaling pathway is shut down by phosphorylation of the NICD subunit by C/Cyclin-dependent kinase 8 (CDK8) and subsequently poly-ubiquitinated by F-box containing protein (FBW7) and degraded via proteasome. The strength and outcome of receptor-ligand binding can be modulated by post-translational modifications of NOTCH receptors, operated by the Fringe family of enzymes.