Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

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

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

J Exp Med 2007
15472075 Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia

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

Science 2004
17646409 FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors

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

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

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

Mol. Cell. Biol. 2006
Participant Of
Name Identifier Synonyms
T-cell leukemia 715
cancer 162 malignant tumor, malignant neoplasm, primary cancer