FBXW7 WD mutants do not bind NICD1

Stable Identifier
R-HSA-2220978
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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FBXW7 (FBW7) mutations are found in ~20% of T-cell acute lymphoblastic leukemia samples. Although a homozygous FBXW7 deletion has been reported, mutations found in FBXW7 are predominantly dominant negative missense mutations that target one of the three highly conserved arginine residues in the WD repeats of FBXW7 (arginines at positions 465, 479 and 505 in the alpha isoform of FBXW7 i.e. positions 347, 361 and 387 in the gamma isoform of FBXW7, as seen in FBXW7alpha R465C i.e. FBXW7gamma R347C, FBXW7alpha R465H i.e. FBXW7gamma R347H, FBXW7alpha R479Q i.e. FBXW7gamma R361Q, FBXW7alpha R505C i.e. FBXW7gamma R387C, and FBXW7alpha R505L i.e. FBXW7gamma R387L). 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). FBXW7 mutations are mutually exclusive with NOTCH1 PEST domain mutations (Thompson et al. 2007, O'Neil et al. 2007).

Besides targeting NICD1 for degradation, FBXW7 also binds and promotes ubiquitination and proteasome-mediated degradation of MYC (Welcker et al. 2004a, Welcker et al. 2004b), a direct NOTCH1 target, as well as cyclin E (Koepp et al. 2001) and JUN (Wei et al. 2005). T-ALL cell lines with FBXW7 mutations are resistant to gamma-secretase inhibitors (GSIs) (Thompson et al. 2007, O'Neil et al. 2007), and in T-ALL patient samples FBXW7 mutations are more frequently detected at relapse than at primary diagnosis (Thompson et al. 2007). The resistance to GSIs in FBXW7 mutant T-ALL cells may be due to sustained MYC activity (Thomspon et al. 2007, O'Neil et al. 2007).

Literature References
PubMed ID Title Journal Year
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
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
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
Normal reaction
Disease
Name Identifier Synonyms
T-cell leukemia 715
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created