F-box and leucine-rich repeat protein 16 (FBXL16)

FBXL16 (F-box and leucine-rich repeat protein 16) is a member of the F-box protein family, characterized by an N-terminal F-box motif for SKP1 binding and C-terminal leucine-rich repeats for substrate engagement. It plays roles in protein ubiquitination and turnover but does not always assemble the canonical SCF E3 ligase complex due to lack of interaction with Cullin 1. Instead, FBXL16 modulates the stability of key regulatory proteins in cancer (such as MYC, β-catenin, SRC3, HIF1α), thereby influencing cell proliferation, migration, drug resistance, and tumorigenesis in a context-dependent manner. In neurodegenerative settings, FBXL16 promotes the degradation of APP and other pathological proteins, potentially improving cognitive function. Its gene expression is regulated by E2F1, linking its activity to cell cycle control and tumor progression. FBXL16 thus represents an emerging, multifaceted therapeutic target with roles in cancer biology, neurodegeneration, and resistance mechanisms to cancer therapies.

Other names

F-box/LRR-repeat protein 16C16orf22FBL16MGC33974Fbl16c380A1.1si:dkey-20j1.3 (zebrafish ortholog)

Depletion or inhibition of FBXL16 increases sensitivity to KRAS inhibitors by downregulating PI3K/AKT signaling in lung cancer. FBXL16 itself acts as a proteasomal degradation facilitator, enhancing ubiquitination and degradation of substrates such as APP, HIF1α, MYC, SRC3.