Fig. 2

Genetic mutations impair FBXW7-mediated oncogene degradation. (a) FBXW7 recognizes its substrate through a conserved CDC4 phosphodegron (CPD) motif, which requires the substrate to be phosphorylated by a kinase. The SCF complex, which consists of SKP1, CUL1, RBX1 and FBXW7, interacts with the substrate through FBXW7 and adds ubiquitin (Ub) to the substrates. Poly-ubiquitinated substrates are then targeted by the proteasome for degradation. (b-d) The FBXW7-substrate interaction can be de-stabilized through: mutations in the substrate that prevent the interaction with FBXW7 (b), mutations in the WD40 domain of FBXW7 that impair its ability to interact with the substrate (c), and mutations in the FBXW7 F-box domain that inhibit its ability to interact with the substrate (d). These mutations have been reported in human cancers and may impair the formation of the SCF complex and stabilize FBXW7 substrates