SCFFBXW7

SCFFBXW7 refers to a specific SCF-type E3 ubiquitin ligase complex that uses FBXW7 as its substrate-recognition subunit. In humans, FBXW7 is encoded by the FBXW7 gene on chromosome 4q31.3 and exists as multiple isoforms, commonly designated FBXW7α, FBXW7β, and FBXW7γ, produced from alternative promoters and differing in localization within the cell.

As part of the SCF complex, FBXW7 binds to phosphorylated degron motifs in target proteins, typically after priming phosphorylation by kinases such as GSK-3 and CK1. Once engaged, the SCFFBXW7 ligase catalyzes ubiquitination of the substrate and directs it to the proteasome for degradation. This activity helps regulate cell cycle progression, differentiation, and developmental signaling by controlling the levels of key regulatory proteins.

Notable substrates of SCFFBXW7 include Cyclin E, c-Myc, Notch intracellular domain, and c-Jun, among others. By promoting their degradation, the complex restrains proliferative signaling and maintains cellular homeostasis. The exact spectrum of substrates can vary by isoform and cellular context.

Clinical significance is largely tied to its role as a tumor suppressor. Somatic mutations or deletions that disrupt the WD40 propeller domain of FBXW7 impair substrate recognition and degradation, leading to stabilization of oncoproteins and enhanced oncogenic potential. FBXW7 is frequently mutated in several cancers, including colorectal, endometrial, pancreatic cancers, and T-cell acute lymphoblastic leukemia, with implications for prognosis and therapy.

Biochemically, FBXW7 is part of the SCF complex with Skp1, CUL1, and RBX1; the WD40 repeats form the substrate-binding domain, while the F-box motif mediates Skp1 binding. The activity of SCFFBXW7 is modulated by cullin neddylation and other regulatory mechanisms, reflecting its integral role in post-translational control of growth-related pathways.