FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation

SCF (complex of SKP1, CUL1 and F-box protein) complexes are ubiquitin ligases that bind to protein substrates and target them for ubiquitylation and subsequent degradation by the proteasome. F-box proteins are the SCF components that recognize specific protein substrates.FBW7 (F-box and WD repeat domain-containing 7) is an F-box protein that binds to key regulators of cell division and growth, including cyclin E, MYC, JUN and Notch. Most FBW7 substrates are proto-oncogenes that are broadly implicated in the pathogenesis of human cancers.FBW7 binds to its substrates after they have been phosphorylated within conserved phospho-degron motifs, called CPDs (Cdc4 phospho-degrons). Substrate phosphorylation is highly regulated. Most substrates are phosphorylated within their CPDs by glycogen synthase kinase 3, a mitogen regulated kinase, and CPDs couple FBW7 activity with mitogenic signalling pathways.FBW7 is a tumour suppressor, and loss of FBW7 function leads to chromosomal instability, probably owing to hyperactivation of its many oncogenic substrates.Mutations in FBW7 occur in diverse human malignancies. FBW7 exhibits an unusual mutational spectrum in tumours, and different types of mutation can have substrate-specific consequences, including dominant-negative effects. Mutations within substrate CPDs are also found in tumours, and provide another mechanism for the oncogenic substrates of FBW7 to evade destruction.