FBXW7

Official Full Name

F-box and WD repeat domain containing 7

Organism

Homo sapiens

GeneID

55294

Background

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations in this gene are detected in ovarian and breast cancer cell lines, implicating the gene's potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

Synonyms

AGO; CDC4; FBW6; FBW7; hAgo; FBX30; FBXW6; SEL10; hCdc4; DEDHIL; FBXO30; SEL-10;

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Detailed Information

FBXW7 (also known as CDC4, FBW6, FBW7, hAgo, Sel10, hCdc4, etc.) is an evolutionary conserved gene which encodes protein that belongs to the F-box family that consisted of estimated 70 proteins in humans. The FBXW7 gene family was initially found to regulate the location of CDK (cyclin recombinase) inhibitor Sic1 in budding yeast and was named Cdc4. Further investigation identified FBXW7 on the human chromosomal region 4q31.3 (200 kDa) for the identification of the human orthologue. FBXW7 gene encodes for three protein isoforms: FBXW7α (the most extensively studied isoform among these three, localizes in the nucleus and is found ubiquitously in tissue), FBXW7β (localizes in the ER/cytoplasm and is found predominantly in brain), FBXW7γ (localizes in the nucleolus and is found in heart and skeletal muscle), each isoform has dimerization domain, sharing ten common exons and differ only at their N-termini by a single isoform-specific first exon. The F-box domain recruits other components of the ubiquitin ligase complex, and WD40 repeatedly binds to the substrate.

Physiological Function

FBXW7, a substrate recognition subunit of the E3 ubiquitin ligase molecule and a part of the SCF/β-TrCP (Skp1-Cdc53/Cullin-F-box-protein) complex, has influence on many pathways and plays pivotal roles in cell division, growth, and is responsible for substrate recognition, which targets multiple transcriptional activators and oncoproteins including Cyclin E, Notch1, Notch4, c-JUN, and c-MYC. FBXW7 binds each of the substrates above through a conserved phosphorylated domain - namely, the Cdc4 phosphodegron. Due to most of these proteins targeted by Fbxw7 for degradation are proto-oncoproteins, Fbxw7 has been conferring the function of a tumor suppressor.

Figure 1. The role of Fbxw7 in protein degradation (Takeishi et al. 2014)

FBXW7 is a haploin-sufficient gene that promotes non-homologous end-joining (NHEJ) repair, and FBXW7 depletion causes radio-sensitization. In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DSB (Double Strand Breaks) sites, such activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, thereby promotes the binding of XRCC4 to FBXW7. And SCFFBXW7 E3 ligase subsequently promotes polyubiquitination of XRCC4 at lysine 296 through lysine 63 linkage to enhance binding to the Ku70/80 complex, as a result, to promoting NHEJ repair. The process demonstrates one mechanism that FBXW7 guarantees genome integrity.

Figure 2. One Mechanism that FBXW7 Contributes to Genome Integrity (Zhang et al. 2016)

The human FBXW7 protein essentially denotes an F-box protein with 8-WD repeats. These key domains enable FBXW7 to perform its function through protein-protein interaction. The F-box domain recruits the SCF complex through direct contact with the adaptor SKP1. The WD40 domain has a binding pocket for phosphorylation degradation that interacts with the phosphorylated substrate. By this procession, FBXW7 bridges the interaction between the substrate and the core SCF, mediating the transfer of ubiquitin from E2 to the target protein for degradation.

FBXW7 Mutation Associated Diseases

Evidences indicated that FBXW7 works as a putative tumor suppressor in human tumorigenesis, meanwhile, FBXW7 inactivation or loss of FBXW7 will subsequently result in genomic instability, and may finally lead to oncogenesis. Heterozygous mutations in FBXW7 have been detected in several types of human cancers. In fact, FBXW7 mutations are found in 6% of tumors making it the 4th most frequently mutated gene, the frequencies are even higher in individual malignancies including cholangiomas (35%), T-cell acute lymphocytic leukemia (31%), colorectal cancer (10%), etc. Most of these mutations are point mutations, which lead to key positions amino-acid substitutions in the WD40 repeats, accordingly, result in the disruption of substrate binding. However, rest of the mutations are mostly nonsense mutations that leads to non-functional Fbxw7. These clinical observations indicate that fbxw7 plays an important role in cell cycle regulation and is as well important for preventing tumorigenesis.

References:

Lan H, Sun Y. FBXW7 E3 ubiquitin ligase: degrading, not degrading, or being degraded. Protein & Cell. 2019.
Yeh C-H, Bellon M, Nicot C. FBXW7: a critical tumor suppressor of human cancers. Molecular Cancer. 2018;17(1):115.
Zhang Q, Karnak D, Tan M, Lawrence TS, Morgan MA, Sun Y. FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4. Molecular Cell. 2016;61(3):419-33.
Takeishi S, Nakayama KI. Role of Fbxw7 in the maintenance of normal stem cells and cancer-initiating cells. British Journal of Cancer. 2014;111(6):1054-9.
Aydin I, Melamed R, Adams S, Castillo-Martin M, Demir A, Bryk D, et al. FBXW7 Mutations in Melanoma and a New Therapeutic Paradigm. Journal of the National Cancer Institute. 2014;106.
S Nateri A. Colorectal Cancer: A Pathology of the Colon-Rectum and A Disease of the Genome. Internal Medicine. 2013;3:1-6.

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