Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants

Stable Identifier
Homo sapiens
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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 (Weng et al. 2004). HD domain mutations enable spontaneous, ligand-independent, proteolytic release of the NICD1 fragment, although mutants remain responsive to ligand binding (Malecki et al. 2006), while PEST domain mutations prolong NICD1 half-life and transcriptional activity through interference with FBXW7 (FBW7)-mediated ubiquitination and degradation (Thompson et al. 2007, O'Neil et al. 2007). NOTCH1 HD+PEST domain mutants annotated here are NOTCH1 L1600P;P2514Rfs*4, NOTCH1 L1600P;Q2440*, NOTCH1 L1600P;Q2395* and NOTCH1 L1574P;P2474Afs*4.

Literature References
PubMed ID Title Journal Year
15472075 Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia

Lee, W, Blacklow, SC, Silverman, LB, Look, AT, Sanchez-Irizarry, C, Aster, JC, Ferrando, AA, Weng, AP, Morris JP, 4th

Science 2004
17646408 The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia

Basso, G, Sulis, ML, Buonamici, S, Thompson, BJ, Aifantis, I, Palomero, T, Vilimas, T, Ferrando, AA

J Exp Med 2007
17646409 FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors

Draetta, G, Rao, S, Sears, R, Strack, P, Tibbitts, D, Hardwick, J, Pieters, R, Look, AT, Welcker, M, Meijerink, JP, Winter, C, Grim, J, O'Neil, J, Clurman, BE

J Exp Med 2007
16738328 Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes

Mitchell, JL, Malecki, MJ, Blacklow, SC, Xu, ML, Sanchez-Irizarry, C, Aster, JC, Histen, G

Mol. Cell. Biol. 2006
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
T-cell acute lymphoblastic leukemia DOID:5603
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