Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants

When found in cis, HD and PEST domain mutations act synergistically, increasing NOTCH1 transcriptional activity up to ~40-fold, compared with up to ~10-fold and up to ~2-fold increase with HD mutations alone and PEST domain mutations alone, respectively. HD domain mutations enable spontaneous, ligand-independent, proteolytic release of the NICD1 fragment, although mutants remain responsive to ligand binding, while PEST domain mutations prolong NICD1 half-life and transcriptional activity through interference with FBXW7 (FBW7)-mediated ubiquitination and degradation. NOTCH1 HD+PEST domain mutants annotated here are NOTCH1 L1600P;P2514Rfs*4, NOTCH1 L1600P;Q2440*, NOTCH1 L1600P;Q2395* and NOTCH1 L1574P;P2474Afs*4.

Summary from Reactome (R-HSA-2894862), read 2026-09-23.