Find NOTCH1 Products Interaction Network for NOTCH1 NOTCH1 Details

Related Pathways Notch Signaling View All Pathways

Synonyms: 9930111A19Rik, hN1, lin-12, Mis6, NICD, NOTCH, NOTCH1, TAN1

Notch Signaling

Notch proteins are involved with microenvironment intercellular cell-fate decisions such as self-renewal (stem-cell), lineage-determination (differentiation) and survival. Abnormally high or low levels of Notch signaling are lethal at the embryonic level. The Notch signaling network is composed of a family of four Notch receptors (Notch1, Notch2, Notch3, Notch4) and five ligands from the Jagged (Jagged-1 and Jagged-2) and Delta (Delta-like-1, Delta-like-3 and Delta-like 4) families plus modifier proteins from the Fringe family (Lunatic, Manic, and Radical Fringe).

Notch signaling typically involves binding between ligands and receptors associated with adjacent cells. The signaling mechanism involves a process of regulated intramembrane proteolysis (RIP) that results in the shedding of the ectodomains of both the ligand and the receptor. This process releases the intracellular domains (ICD) of the ligand and receptor, and allows their translocation to respective nuclei where they regulate gene expression. The Notch ICD (NICD) converts the transcription factor CBF1/CSL from a gene repressor to a gene activator.

Notch proteins are single-pass transmembrane receptors with an extracellular (EC) domain composed of multiple epidermal growth factor-like repeats (EGF-like) with embedded ligand binding sites. The cytoplasmic region contains the RAM domain, seven ankyrin repeats, and a C-terminal PEST domain. The mechanism of signaling involves the binding of a ligand to the Notch receptor followed by the activation of a metalloprotease, ADAM (a disintegrin and metalloprotease)-type protease (ADAM 10/kuz and/or ADAM 17/TACE) which cleaves just external to the transmembrane domain and releases the ectodomain. The NICD is release by subsequent cleavage within the transmembrane domain (TM) of the Notch receptor. The TM domain cleavage is mediated by the catalytic subunit, presenilin, of the gamma-secretase (γ-secretase) membrane protein complex which also contains nicastrin, APH-1 and PEN-2.