Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling

Stable Identifier
R-HSA-2644607
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

Loss of function mutations found in FBXW7 in T-cell acute lymphoblastic leukemia are predominantly dominant negative missense mutations that target one of the three highly conserved arginine residues in the WD repeats of FBXW7 (Thompson et al. 2007, O'Neil et al. 2007). These three arginine residues are part of the FBXW7 substrate binding pocket and each one of them contacts the phosphorylated threonine residue in the conserved substrate phosphodegron region (Orlicky et al. 2003). Specifically, FBXW7 interacts with the PEST domain of NOTCH1 upon phosphorylation of the PEST domain by CDK8 (Fryer et al. 2004). FBXW7 mutants are therefore unable to bind and promote ubiquitination of the NOTCH1 intracellular domain (NICD1), leading to prolonged NICD1 transcriptional activity (Thompson et al. 2007, O'Neil et al. 2007).

Literature References
PubMed ID Title Journal Year
15546612 Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover

Fryer, CJ, White, JB, Jones, KA

Mol Cell 2004
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
12553912 Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase

Orlicky, S, Tang, X, Willems, A, Tyers, M, Sicheri, F

Cell 2003
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
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed