Constitutive Signaling by NOTCH1 PEST Domain Mutants

Stable Identifier
Homo sapiens
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As NOTCH1 PEST domain is intracellular, NOTCH1 PEST domain mutants are expected to behave as the wild-type NOTCH1 with respect to ligand binding and proteolytic cleavage mediated activation of signaling. However, once the NICD1 fragment of NOTCH1 is released, PEST domain mutations prolong its half-life and transcriptional activity through interference with FBXW7 (FBW7)-mediated ubiquitination and degradation of NICD1 (Weng et al. 2004, Thompson et al. 2007, O'Neil et al. 2007). All NOTCH1 PEST domain mutants annotated here (NOTCH1 Q2395*, NOTCH1 Q2440*, NOTCH1 P2474Afs*4 and NOTCH1 P2514Rfs*4) either have a truncated PEST domain or lack the PEST domain completely.
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
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
T-cell acute lymphoblastic leukemia DOID:5603
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