(13/n): in Type 2, transcription starts aberrantly at exon 1 or 2 but splices directly into exon 25 due to a deletion, both ultimately producing a truncated NOTCH1 protein that includes the active ICN1 domain.

(10/n): In contrast, PEST domain mutations cause ligand-independent activation and impair proteasomal degradation of the intracellular NOTCH1, leading to sustained transcription of NOTCH1 target genes and contributing to leukemogenesis.

(7/n): ICN1 translocate to the nucleus, forms a transcriptional activation complex with RBPJ and MAML1 to drive expression of NOTCH1 target genes, and is ultimately ubiquitinated by FBXW7 and degraded by the proteasome to terminate signalling.

(5/n): for signal transduction and degradation. The mapped exonic organisation indicates that exons 1–25 encode the extracellular domain, exons 26–27 span the transmembrane region, and exons 28–34 encode the intracellular domain (ICN) that mediates transcriptional activation after cleavage.