NOTCH1 Gene: Function, Mutations, and Associated Diseases | Biomedical Resource

NOTCH1 encodes a member of the Notch family of transmembrane receptors. The protein is synthesized as a single precursor that is cleaved to form a heterodimer. Upon ligand binding, the receptor undergoes a series of proteolytic cleavages that release the intracellular domain (NICD), which translocates to the nucleus and regulates transcription. NOTCH1 signaling is critical for cell fate determination, proliferation, and apoptosis during development and adult tissue homeostasis. Mutations in NOTCH1 are associated with various cancers, particularly T-cell acute lymphoblastic leukemia (T-ALL), and developmental disorders such as Adams-Oliver syndrome and aortic valve disease.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Notch signaling pathway

• Signaling by NOTCH1

• Regulation of stem cell pluripotency

• T-cell receptor signaling pathway

• Hematopoietic cell lineage

The NOTCH1 protein is a 2555-amino acid single-pass type I transmembrane receptor. It is synthesized as a 300 kDa precursor that is cleaved by furin into a 180 kDa N-terminal extracellular domain and a 120 kDa C-terminal transmembrane fragment, which remain non-covalently associated. The extracellular domain contains 36 EGF-like repeats and 3 LIN12/Notch repeats, while the intracellular domain includes a RAM domain, ankyrin repeats, a transactivation domain, and a PEST sequence. Ligand binding (e.g., Delta-like, Jagged) triggers two proteolytic cleavages (ADAM metalloprotease and gamma-secretase) that release the NICD, which translocates to the nucleus and forms a complex with RBPJ and MAML to activate transcription of target genes such as MYC and HES1.