FBXL8

FBXL8 (F-box/LRR-repeat protein 8, FBL8) is a member of the FBXL subfamily of F-box proteins. It has an N-terminal F-box domain through which it docks onto the SKP1 adaptor and, via SKP1, onto CUL1 and the catalytic RING subunit RBX1, assembling a Cullin-RING (SCF) E3 ubiquitin ligase in which the F-box protein serves as the substrate-recognition subunit. Despite the "LRR" in its name, UniProt notes that FBXL8 does not actually contain canonical leucine-rich repeats; nonetheless its C-terminal substrate-binding region is functionally required for substrate engagement (deletion of either the F-box or the C-terminal region abolishes substrate turnover). FBXL8 acts as the substrate-recognition subunit of SCF-FBXL8 and targets several substrates in a strongly context-dependent manner: it promotes ubiquitination and proteasomal degradation of the tumor suppressor p53 (in colorectal cancer), of Thr283- phosphorylated cyclin D3 (CCND3) (in lymphoma), of Snail1 (in post-myocardial- infarction cardiac fibroblasts, dampening RhoA signaling and myofibroblast differentiation), and of unphosphorylated c-MYC (a distinct c-MYC pool from that controlled by FBXW7, with reported heterotypic K48/K63 chains); CCND2 and IRF5 are additional candidate substrates accumulating upon FBXL8 knockdown. Reported localization is predominantly cytoplasmic (loss of FBXL8 causes nuclear c-MYC accumulation), and in heart FBXL8 is enriched in cardiac fibroblasts. Its net effect is context-dependent rather than uniformly oncogenic or tumor-suppressive: oncogenic in colorectal and breast cancer, but tumor-suppressive in lymphoma and anti-fibrotic after myocardial infarction.