VBP1 modulates Wnt/β-catenin signaling by mediating the stability of the transcription factors TCF/LEFs

Abstract

The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor/lymphoid enhancer factor (TCF/LEF), serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL, and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provided mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm

“…Because of the involvement of this pathway in various diseases, present efforts in the drug development field are aimed at identifying inhibitors of the b-catenin-TCF7L2 interactions 73 and the design of specific approaches targeting TCF7L2 stability. 74 Our findings here highlight a potential path for TCF7L2 as a target for intervention in individuals with TAA or for possible prevention in individuals at risk of TAA.…”

ARHGAP10 inhibits the epithelial–mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3β signaling pathway

“…Phosphorylated Akt (p-Akt) can phosphorylate GSK3β and inhibit its kinase activity, leading to the inactivation of GSK3β [ 39 ]. Decreased GSK3β alleviates restraint on β-catenin [ 40 ], contributing to the accumulated β-catenin entry into the nucleus to activate gene transcription and interacts with TCF/LEF and ultimately triggers the transcription of target genes including snail [ 41 , 42 ]. As a direct downstream gene of snail, the expression of epithelial biomarker E-cadherin was significantly downregulated (Fig.…”

VBP1 negatively regulates CHIP and selectively inhibits the activity of hypoxia-inducible factor (HIF)-1α but not HIF-2α

“…This suggested that VBP1 did not regulate HIF-1α protein synthesis. We and others have shown that VBP1 induced ubiquitination of the HIF-1α protein in cultured cells ( 29 , 30 ). Surprisingly, MG132 (a proteasomal inhibitor) treatment only partly rescued VBP1-mediated HIF-1α degradation ( Fig.…”

“…Furthermore, VBP1 facilitates proteasomal and autophagy-mediated degradation of hMSH4 ( 28 ). We recently reported that VBP1 modulates Wnt/β-catenin signaling by mediating the stability of TCF/LEFs ( 29 ). A recent study reported that VBP1 facilitates HIF-1α degradation by stabilizing pVHL ( 30 ).…”