Fbw7

FBW7, also known as FBXW7 or hCDC4, is a member of the F-box protein family and serves as the substrate recognition component of the SKP1-CUL1-F-box protein (SCF) E3 ubiquitin ligase complex. It binds specific phosphorylated degron motifs in target proteins and promotes their ubiquitination and subsequent proteasomal degradation. Through this function, FBW7 regulates the stability of several key oncoproteins, including cyclin E, c-Myc, Notch intracellular domain, c-Jun, and MCL1, thereby influencing cell cycle progression, differentiation, and apoptosis.

FBXW7 contains WD40 repeats that form a beta-propeller structure responsible for substrate binding. It exists in three main isoforms—FBXW7α, FBXW7β, and FBXW7γ—produced by alternative transcription start sites. These isoforms differ in their N-terminal regions and subcellular localization, with FBXW7α primarily nuclear, FBXW7β more cytoplasmic, and FBXW7γ associated with the nucleolus, while sharing the WD40 domain that mediates substrate recognition.

Genomic and clinical significance: The FBXW7 gene is located on chromosome 4q31.3. FBW7 functions as a tumor suppressor, and loss-of-function mutations or deletions are common across a range of cancers, including T-cell acute lymphoblastic leukemia (T-ALL), glioblastoma, colorectal, endometrial, and gastric cancers. Most cancer-associated mutations cluster in the WD40 domain, impairing substrate binding and leading to stabilization of oncogenic proteins. This contributes to tumorigenesis and can influence responses to therapy.

Regulation and mechanism: Phosphorylation of substrate degrons by kinases such as GSK3β and CDKs primes recognition by FBW7. As part of the SCF complex, FBW7 functions alongside SKP1, CUL1, and RBX1 to coordinate ubiquitination and degradation of target proteins in response to cellular signals.