Β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling. Issue 8 (17th August 2017)

• Record Type: Journal Article
• Authors: Long, Marcus John; Lin, Hong-Yu; Parvez, Saba; Zhao, Yi; Poganik, Jesse Richard; Huang, Paul; Aye, Yimon
• Is Part Of: Cell chemical biology. Volume 24:Issue 8(2017)
• Page Start: 944
• Page End: 957.e7
• Publication Date: 2017-08-17
• Subjects: redox signaling -- reactive electrophile response -- β-catenin/wnt signaling -- Keap1-Nrf2-antioxidant response -- signaling crosstalk -- 4-hydroxynonenal -- β-TrCP -- HaloTag; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.06.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between β-catenin N terminus and β-TrCP1 (an antagonist of both Nrf2 and β-catenin), and independent of binding between Nrf2 and β-TrCP1. Intriguingly, β-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of β-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis. Graphical Abstract: Highlights: Antioxidant response (AR) negatively regulates Wnt signaling Loss of β-TRCP1 binding at β-catenin N terminus sensitizes Wnt to AR inhibition β-catenin upregulates AR, irrespective of the extent to which β-TRCP binds β-catenin The delicate balance between Wnt and AR may be exploitable for drug discovery Abstract : Upregulation of β-catenin activity promotes Wnt-dependent oncogenesis. β-Catenin upregulation often occurs through mutation in its N terminus, which binds β-TrCP. Long et al. show that modification of the β-catenin N terminus also sensitizes cells to Nrf2-mediated inhibition of Wnt signaling. This acquired susceptibility may be exploitable for cancer therapy.