Figure 2.

Proposed mechanism of malignant transformation mediated by Fbw7 mutations. Somatic missense mutations in any of the three critical arginine residues (Arg⁴⁶⁵, Arg⁴⁷⁹ or Arg⁵⁰⁵) within the WD40 domain of Fbw7 abrogate its interaction with Cdc4 phospho degron (CPD) motifs on target substrates. Phosphorylated substrates are no longer bound and polyubiquitnated by SCF^Fbw7 and accumulate in the nucleus. Accumulation of Fbw7 targets, such a c-Myc, cyclin E and Notch-1, can trigger oncogene-induced apoptosis and senescence, which is largely dependent on p53 status. Cells harboring mutations in Fbw7 are selectively pressured to inactivate p53 for continued proliferation and survival, ultimately leading to increased genomic instability and tumorigenesis.