β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Marcus John Long; Hong Yu Lin; Saba Parvez; Yi Zhao; Jesse Richard Poganik; Paul Huang; Yimon Aye

doi:10.1016/j.chembiol.2017.06.009

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Marcus John Long, Hong Yu Lin, Saba Parvez, Yi Zhao, Jesse Richard Poganik, Paul Huang, Yimon Aye^*

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	944-957.e7
Journal	Cell Chemical Biology
Volume	24
Issue number	8
DOIs	https://doi.org/10.1016/j.chembiol.2017.06.009
State	Published - Aug 17 2017

Funding

We thank Prof. Andrew Grimson and Dr. Rene Giessler for lentiviral-based shRNA technique transfer and Sanjna L. Surya for TEV protease. Research, instrumentation, and personnel in this work are partly or fully supported by NSF CAREER (CHE-1351400), NIH New Innovator (1DP2GM114850), Sloan Fellowship (FG-2016-6379), Beckman Young Investigator, ONR Young Investigator (N00014-17-1-2529) (Y.A); HHMI Fellowship (S.P.); NIH CBI Fellowship (T32GM008500) (J.R.P.). Core facility support: NSF-MRI (CHE-1531632, PI: Y.A.) for NMR; flow cytometry (ESSCF, NYS-DOH, contract #C026718) and imaging (NIH 1S10RR025502, PI: R.M. Williams).

Keywords

4-hydroxynonenal
HaloTag
Keap1-Nrf2-antioxidant response
reactive electrophile response
redox signaling
signaling crosstalk
β-TrCP
β-catenin/wnt signaling

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2017.06.009

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title = "β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling",

abstract = "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.",

keywords = "4-hydroxynonenal, HaloTag, Keap1-Nrf2-antioxidant response, reactive electrophile response, redox signaling, signaling crosstalk, β-TrCP, β-catenin/wnt signaling",

author = "Long, {Marcus John} and Lin, {Hong Yu} and Saba Parvez and Yi Zhao and Poganik, {Jesse Richard} and Paul Huang and Yimon Aye",

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doi = "10.1016/j.chembiol.2017.06.009",

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AU - Parvez, Saba

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AU - Huang, Paul

AU - Aye, Yimon

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N2 - 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.

AB - 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.

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β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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