FBXW7

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. Three transcript variants encoding three different isoforms have been found for this gene. [provided by RefSeq]

F-box and WD repeat domain containing 7

Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22748924, PubMed:17434132, PubMed:26976582, PubMed:28727686).

Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter bring them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:26774286, PubMed:17434132, PubMed:26976582, PubMed:28727686).

Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686).

Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463).

Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593).

Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018).

Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286).

The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286).

Cellular response to DNA damage stimulus Source: UniProtKB
Cellular response to UV Source: UniProtKB
Lipid homeostasis Source: BHF-UCL
Lung development Source: Ensembl
Negative regulation of gene expression Source: BHF-UCL
Negative regulation of hepatocyte proliferation Source: BHF-UCL
Negative regulation of Notch signaling pathway Source: BHF-UCL
Negative regulation of osteoclast development Source: UniProtKB
Negative regulation of RNA polymerase II regulatory region sequence-specific DNA binding Source: Ensembl
Negative regulation of SREBP signaling pathway Source: BHF-UCL
Negative regulation of triglyceride biosynthetic process Source: BHF-UCL
Notch signaling pathway Source: Ensembl
Positive regulation of epidermal growth factor-activated receptor activity Source: BHF-UCL
Positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
Positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
Positive regulation of proteasomal protein catabolic process Source: ParkinsonsUK-UCL
Positive regulation of protein targeting to mitochondrion Source: ParkinsonsUK-UCL
Positive regulation of protein ubiquitination Source: ParkinsonsUK-UCL
Positive regulation of ubiquitin-dependent protein catabolic process Source: BHF-UCL
Positive regulation of ubiquitin-protein transferase activity Source: ParkinsonsUK-UCL
Proteasome-mediated ubiquitin-dependent protein catabolic process Source: ARUK-UCL
Protein destabilization Source: Ensembl
Protein stabilization Source: BHF-UCL
Protein ubiquitination Source: UniProtKB
Regulation of autophagy of mitochondrion Source: ParkinsonsUK-UCL
Regulation of cell cycle G1/S phase transition Source: ParkinsonsUK-UCL
Regulation of cell migration involved in sprouting angiogenesis Source: Ensembl
Regulation of circadian rhythm Source: UniProtKB
Regulation of lipid storage Source: BHF-UCL
Regulation of protein localization Source: BHF-UCL
Rhythmic process Source: UniProtKB-KW
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
Sister chromatid cohesion Source: BHF-UCL
Ubiquitin recycling Source: GO_Central
Vasculature development Source: BHF-UCL
Vasculogenesis Source: Ensembl

Isoform 1: Nucleoplasm; Chromosome. Localizes to site of double-strand breaks following phosphorylation by ATM.
Isoform 2: Cytoplasm
Isoform 3: Nucleolus

Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4 (PubMed:26774286).
Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation (PubMed:22608923).