Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase

Sajjan Koirala; Jonathon Klein; Yumei Zheng; Nicole O. Glenn; Travis Eisemann; Klementina Fon Tacer; Darcie J. Miller; Ozlem Kulak; Meifen Lu; David B. Finkelstein; Geoffrey Neale; Heather Tillman; Peter Vogel; Douglas W. Strand; Lawrence Lum; Chad A. Brautigam; John M. Pascal; Wilson K. Clements; Patrick R Potts

doi:10.1016/j.celrep.2020.107922

Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase

Sajjan Koirala, Jonathon Klein, Yumei Zheng, Nicole O. Glenn, Travis Eisemann, Klementina Fon Tacer, Darcie J. Miller, Ozlem Kulak, Meifen Lu, David B. Finkelstein, Geoffrey Neale, Heather Tillman, Peter Vogel, Douglas W. Strand, Lawrence Lum, Chad A. Brautigam, John M. Pascal, Wilson K. Clements, Patrick R Potts

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

8 Scopus citations

Abstract

Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway.

Original language	English (US)
Article number	107922
Journal	Cell Reports
Volume	32
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2020.107922
State	Published - Jul 21 2020

Keywords

Axin
PAGE4
PARylation
RNF146
TNKS
Tankyrase
Wnt
cancer-testis antigen
prostate
β-catenin

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2020.107922

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Koirala, S., Klein, J., Zheng, Y., Glenn, N. O., Eisemann, T., Fon Tacer, K., Miller, D. J., Kulak, O., Lu, M., Finkelstein, D. B., Neale, G., Tillman, H., Vogel, P., Strand, D. W., Lum, L., Brautigam, C. A., Pascal, J. M., Clements, W. K., & Potts, P. R. (2020). Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase. Cell Reports, 32(3), Article 107922. https://doi.org/10.1016/j.celrep.2020.107922

Koirala, S, Klein, J, Zheng, Y, Glenn, NO, Eisemann, T, Fon Tacer, K, Miller, DJ, Kulak, O, Lu, M, Finkelstein, DB, Neale, G, Tillman, H, Vogel, P, Strand, DW , Lum, L , Brautigam, CA, Pascal, JM, Clements, WK & Potts, PR 2020, 'Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase', Cell Reports, vol. 32, no. 3, 107922. https://doi.org/10.1016/j.celrep.2020.107922

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title = "Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase",

abstract = "Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway.",

keywords = "Axin, PAGE4, PARylation, RNF146, TNKS, Tankyrase, Wnt, cancer-testis antigen, prostate, β-catenin",

author = "Sajjan Koirala and Jonathon Klein and Yumei Zheng and Glenn, {Nicole O.} and Travis Eisemann and {Fon Tacer}, Klementina and Miller, {Darcie J.} and Ozlem Kulak and Meifen Lu and Finkelstein, {David B.} and Geoffrey Neale and Heather Tillman and Peter Vogel and Strand, {Douglas W.} and Lawrence Lum and Brautigam, {Chad A.} and Pascal, {John M.} and Clements, {Wilson K.} and Potts, {Patrick R}",

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year = "2020",

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doi = "10.1016/j.celrep.2020.107922",

language = "English (US)",

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AU - Koirala, Sajjan

AU - Klein, Jonathon

AU - Zheng, Yumei

AU - Glenn, Nicole O.

AU - Eisemann, Travis

AU - Fon Tacer, Klementina

AU - Miller, Darcie J.

AU - Kulak, Ozlem

AU - Lu, Meifen

AU - Finkelstein, David B.

AU - Neale, Geoffrey

AU - Tillman, Heather

AU - Vogel, Peter

AU - Strand, Douglas W.

AU - Lum, Lawrence

AU - Brautigam, Chad A.

AU - Pascal, John M.

AU - Clements, Wilson K.

AU - Potts, Patrick R

PY - 2020/7/21

Y1 - 2020/7/21

N2 - Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway.

AB - Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/β-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/β-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/β-catenin pathway.

KW - Axin

KW - PAGE4

KW - PARylation

KW - RNF146

KW - TNKS

KW - Tankyrase

KW - Wnt

KW - cancer-testis antigen

KW - prostate

KW - β-catenin

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SN - 2211-1247

VL - 32

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 107922

ER -

Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase

Abstract

Keywords

ASJC Scopus subject areas

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