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The F‐box Protein FBXL16 Upregulates the Stability of c‐myc Oncoprotein by Antagonizing FBW7 Function
Author(s) -
Morel Marion,
Shah Krushangi,
Long Weiwen
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03047
Subject(s) - skp1 , ubiquitin ligase , f box protein , ubiquitin , downregulation and upregulation , biology , ubiquitin protein ligases , scaffold protein , carcinogenesis , ddb1 , microbiology and biotechnology , cancer research , chemistry , genetics , cancer , signal transduction , gene
F‐box proteins are essential components of the SCF (SKP1‐CUL1‐F‐box) E3 ubiquitin ligases as they are responsible for substrate recognition. F‐box proteins bind to SKP1 through the F‐box motif and bring the substrate to the E3 ligase complex for ubiquitination. So far, 69 F‐box proteins have been identified in humans, and they fall into 3 families depending on their substrate recognition domains: FBXLs (Leucine‐Rich Repeats or LRR), FBXWs (WD repeats) and FBXOs (Other domains). FBXL16 is a poorly studied F‐box protein, which was shown to be a transcriptional target of E2F1 (Sato et al, 2010). As it doesn’t interact with the scaffold protein Cul1, FBXL16 might not form a functional SCF‐E3 ligase complex (Honarpour et al, 2014). In our present study, we found by data mining that FBXL16 is highly upregulated in many cancers, and its upregulation is often associated with poor patient survival, indicating that FBXL16 may play important roles in cancers. To decipher the role of FBXL16 in oncogenesis, we first analyzed its biochemical function in regulating protein levels of different SCF‐E3 substrates. Unexpectedly, we found that FBXL16 upregulates oncogenic proteins targeted by SCF‐E3 ligases, such as Steroid Receptor Coactivator 3 (SRC‐3) and c‐myc. Here, we have focused on c‐myc, a well‐known oncoprotein overexpressed in most human cancers, and found that FBXL16 interacts with and stabilizes c‐myc protein. This stabilization is dependent on c‐myc phosphorylation on both Threonine 58 and Serine 62, the phosphodegron recognized by FBW7 for its subsequent ubiquitination. Further, we found that FBXL16 antagonizes FBW7‐E3 ligase activity, leading to reduced c‐myc ubiquitination. In line with its role in upregulating the levels of oncoproteins, we found that FBXL16 promotes cancer cell growth and migration. Taken together, our findings reveal FBXL16 as a unique F‐Box protein antagonizing the activity of another F‐box protein FBW7 and as a new positive regulator of c‐myc. Further investigation is being carried out to determine the oncogenic roles of FBXL16 in vivo and may unravel FBXL16 as a new therapeutic target of cancers. Support or Funding Information This research was supported by NCI of the National Institutes of Health under award number R01CA193264.