Neurogenic locus notch homolog protein 1 (NOTCH1) (NOTCH1)

Neurogenic locus notch homolog protein 1 (NOTCH1) is a single-pass transmembrane receptor that serves as a critical mediator of cell-to-cell communication and cell fate determination (UniProt Consortium, 2024). Upon binding to ligands such as Delta-like or Jagged on adjacent cells, NOTCH1 undergoes sequential proteolytic cleavages, culminating in the release of the Notch intracellular domain (NICD) by the gamma-secretase complex (Siebel & Lendahl, 2017). The NICD then translocates to the nucleus, where it associates with the DNA-binding protein RBPJ to activate the transcription of target genes like HES1 and MYC, which regulate cell proliferation and differentiation (Aster et al., 2017). Dysregulation of NOTCH1 signaling is a primary driver in various malignancies, most notably T-cell acute lymphoblastic leukemia (T-ALL), where activating mutations are found in over 50% of cases (Weng et al., 2004). Therapeutic interventions primarily focus on gamma-secretase inhibitors (GSIs) and monoclonal antibodies designed to block receptor activation or ligand binding (Takebe et al., 2014). However, the clinical development of these agents has been significantly challenged by dose-limiting gastrointestinal toxicity, resulting from the essential role of NOTCH1 in maintaining the balance between secretory and absorptive cells in the intestinal epithelium (van Es et al., 2005).

Other names

Notch 1hN1TAN1Translocation-associated notch protein humanAOS5AOVD1

Inhibition of the gamma-secretase complex to prevent the release of the Notch intracellular domain (NICD), or use of monoclonal antibodies to block ligand binding or receptor activation.