F-box and leucine-rich repeat protein 2 (FBXL2)

F-box and leucine-rich repeat protein 2 (FBXL2) is an F-box protein that serves as a substrate recognition subunit of the SCF (SKP1-cullin-F-box) E3 ubiquitin ligase complex, targeting specific proteins for ubiquitin-dependent proteasomal degradation[3][1][5]. It belongs to the Fbls class of the F-box protein family, characterized by 12 tandem leucine-rich repeats, and contains a CaaX motif that undergoes geranylgeranylation, targeting it to cellular membranes. FBXL2 is involved in the regulation of several cellular pathways, including the degradation of cyclins (such as CCND2, CCND3), regulatory subunits of phosphoinositide 3-kinases (notably p85β), and proteins involved in calcium signaling (IP3R3) and inflammation (TRAF family, NLRP3 inflammasome). Through these mechanisms, FBXL2 participates in controlling cell cycle progression, apoptosis, autophagy, and immune responses. Aberrant regulation or activity of FBXL2 has been associated with cancer, inflammation, and viral infection[1][3][5]. Its activity can be antagonized by calmodulin and tumor suppressors like PTEN, which influence substrate choice and degradation efficiency[1][3]. The small-molecule inhibitor GGTi-2418 represents a drug that targets FBXL2's post-translational modification, disrupting its function[1].

Other names

FBL2FBL3F-box/LRR-repeat protein 2F-box and leucine rich repeat protein 2F-box protein FBL2/FBL3F-box protein containing leucine-rich repeats

Inhibition of FBXL2 geranylgeranylation (e.g., by GGTi-2418), disrupting its membrane localization and ability to mediate substrate ubiquitination and degradation