Constitutive Signaling by NOTCH1 PEST Domain Mutants

Stable Identifier
R-HSA-2644606
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

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
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
Participants
Participant Of
Disease
Name Identifier Synonyms
T-cell leukemia 715
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed