FBXW9

FBXW9 is a member of the F-box/WD40 (FBXW) family of proteins, containing an N-terminal F-box motif and a C-terminal beta-propeller built from seven WD40 repeats. F-box proteins serve as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif binds SKP1 (which in turn bridges to CUL1 and the RBX1-bound catalytic RING), while the WD40 propeller engages substrate proteins and presents them for ubiquitination, marking them for proteasomal degradation. FBXW9 is itself non-catalytic: it acts as a substrate adaptor, with the ubiquitin-transfer (RING) activity contributed by RBX1 in the assembled SCF. FBXW9 has been shown experimentally to bind SKP1 (array MAPPIT screen with co-immunoprecipitation validation) and to co-purify with CUL1 in affinity purification-mass spectrometry of SCF assemblies, and ComplexPortal assigns it as the variable substrate-receptor subunit of an SCF complex variant. It is broadly expressed and undergoes N-terminal phosphorylation at several residues. FBXW9 remains poorly characterized at the level of direct biochemistry: no endogenous ubiquitination substrate has been validated by direct ubiquitination or degradation assays. Cancer-focused studies place FBXW9 transcription downstream of p53 (a direct p53 target gene) and of CREB in an IGFBP5-ROR1/HER2 signaling axis, and report cell-cycle/proliferation phenotypes on knockdown in breast cancer and invasion phenotypes in glioblastoma stem-like cells; however, candidate substrates such as TP53 remain predicted rather than biochemically demonstrated, so FBXW9's assigned molecular and process roles still rest largely on family-level inference.