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

Key Points

  • 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.

Abstract

FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCFFBW7 degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.

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Figure 1: Schematic of an E3 SCF (complex of SKP1, CUL1 and F-box protein) ubiquitin ligase.
Figure 2: The organization of the FBW7 gene and its protein isoforms.
Figure 3: Phosphorylation-dependent cyclin E turnover through its C-terminal degron.
Figure 4: Speculative model for FBW7 dimer-dependent cyclin E turnover.
Figure 5: The substrates of FBW7.
Figure 6: Consequences of heterozygous mutations in FBW7.

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Acknowledgements

We thank all members of the Clurman laboratory for critical reading of this manuscript, as well as the Leukemia and Lymphoma Society (M.W.) and the US National Institutes of Health (B.E.C.) for funding. B.E.C. is a Burroughs Wellcome Fund clinical scientist in translational research.

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Correspondence to Markus Welcker.

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National Cancer Institute

bladder cancer

bone cancer

breast cancer

Burkitt lymphoma

colon cancer

endometrial cancer

gastric cancer

leukaemia

liver cancer

lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

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Welcker, M., Clurman, B. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer 8, 83–93 (2008). https://doi.org/10.1038/nrc2290

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