SCFFbw7

SCFFbw7, or Skp1-Cullin-1-F-box protein 7, is an E3 ubiquitin ligase complex of the SCF (Skp1-Cullin-F-box) family. It marks a subset of regulatory proteins for ubiquitin-mediated proteasomal degradation, contributing to protein turnover that governs cell cycle progression and differentiation. The core complex consists of Skp1, Cullin-1 (CUL1), Rbx1, and the F-box adaptor Fbw7, which is encoded by the FBXW7 gene. Alternative transcription yields three main isoforms—Fbw7α, Fbw7β, and Fbw7γ—localizing to the nucleus, cytoplasm, and nucleolus, respectively, and directing substrate access to distinct cellular compartments.

Substrate recognition is mediated by the WD40-repeat domain of Fbw7, which binds phosphorylated degrons known as Cdc4 phosphodegrons (CPDs). Phosphorylation by CDKs and, in some cases, GSK3 primes substrates for binding. Upon recognition, the SCFFbw7 complex catalyzes ubiquitination of the target protein, marking it for destruction by the 26S proteasome.

Key substrates include Cyclin E (CCNE1), c-Myc, Notch intracellular domain (NICD), c-Jun, and Mcl-1, among others. Through targeted degradation, SCFFbw7 helps regulate cell cycle transitions, differentiation, and genomic stability, and acts as a barrier to uncontrolled proliferation.

FBXW7 functions as a tumor suppressor gene. Somatic mutations, deletions, and reduced expression of FBXW7 have been reported in several human cancers, including colorectal, endometrial, and pancreatic cancers. Most cancer-associated alterations affect the WD40 substrate-binding domain, leading to stabilization of oncogenic substrates and contributing to tumorigenesis.

Regulation of SCFFbw7 activity involves CUL1 neddylation, coordination with other SCF components, and subcellular localization of the isoforms, all of which influence substrate access and degradation efficiency.