Abstract
FBXW2 inhibits proliferation of lung cancer cells by targeting SKP2 for degradation. Whether and how FBXW2 regulates tumor invasion and metastasis is previously unknown. Here, we report that FBXW2 is an E3 ligase for β-catenin. FBXW2 binds to β-catenin upon EGF-AKT1-mediated phosphorylation on Ser552, and promotes its ubiquitylation and degradation. FBXW2 overexpression reduces β-catenin levels and protein half-life, whereas FBXW2 knockdown increases β-catenin levels, protein half-life and transcriptional activity. Functionally, FBXW2 overexpression inhibits migration and invasion by blocking transactivation of MMPs driven by β-catenin, whereas FXBW2 knockdown promotes migration, invasion and metastasis both in vitro and in vivo lung cancer models. In human lung cancer specimens, while FBXW2 levels are inversely correlated with β-catenin levels and lymph-node metastasis, lower FBXW2 coupled with higher β-catenin, predict a worse patient survival. Collectively, our study demonstrates that FBXW2 inhibits tumor migration, invasion and metastasis in lung cancer cells by targeting β-catenin for degradation.
Highlights
FBXW2 inhibits proliferation of lung cancer cells by targeting SKP2 for degradation
Using IP pull-down assay in variety of human cell lines, including H1299, H358, MDA-MB231, Human embryonic kidney 293 (HEK293), and HeLa cells, we detected endogenous β-catenin and SKP2 proteins in FBXW2 immunoprecipitants, and endogenous FBXW2 and β-TrCP1 in β-catenin immunoprecipitants, respectively
While FBXW2 failed to bind to two β-catenin mutants (β-catenin-S552A, β-catenin-3A), β-TrCP1 bound to them well as to WT β-catenin (Fig. 1f and Supplementary Figure 4f). These results clearly demonstrated that FBXW2mediated β-catenin degradation is independent of glycogen synthase kinase-3β (GSK-3β)/βTrCP1, but dependent on AKT1, whereas β-TrCP1-mediated βcatenin degradation is independent of AKT1/FBXW2, but dependent on Wnt3a/GSK-3β
Summary
FBXW2 inhibits proliferation of lung cancer cells by targeting SKP2 for degradation. FBXW2 overexpression inhibits migration and invasion by blocking transactivation of MMPs driven by β-catenin, whereas FXBW2 knockdown promotes migration, invasion and metastasis both in vitro and in vivo lung cancer models. In human lung cancer specimens, while FBXW2 levels are inversely correlated with β-catenin levels and lymph-node metastasis, lower FBXW2 coupled with higher β-catenin, predict a worse patient survival. Our study demonstrates that FBXW2 inhibits tumor migration, invasion and metastasis in lung cancer cells by targeting β-catenin for degradation. 2), a poorly characterized F-box protein, acts as a tumor suppressor to inhibit growth and survival of lung cancer cells[4]. FBXW2, one of the 69 F-box proteins, functions as a substrate recognition receptor in the SCF (SKP1-Cullin1-F-box protein) ubiquitin ligase complexes[5]. While Cullin and RING protein are required for ligase activity, the F-box protein determines the substrate specificity
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