PUBLICATION
Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase
- Authors
- 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.
- ID
- ZDB-PUB-200724-17
- Date
- 2020
- Source
- Cell Reports 32: 107922 (Journal)
- Registered Authors
- Clements, Wilson, Glenn, Nikki
- Keywords
- Axin, PAGE4, PARylation, RNF146, TNKS, Tankyrase, Wnt, cancer-testis antigen, prostate, β-catenin
- MeSH Terms
-
- Amino Acid Motifs
- Amino Acid Sequence
- Animals
- Antigens, Neoplasm/chemistry
- Antigens, Neoplasm/metabolism*
- Axin Protein
- Fibroblasts/metabolism
- HEK293 Cells
- Humans
- Male
- Mice, Knockout
- Models, Biological
- Organ Specificity*
- Poly ADP Ribosylation
- Prostate/metabolism
- Protein Domains
- Proteolysis
- Stromal Cells/metabolism
- Substrate Specificity
- Tankyrases/antagonists & inhibitors*
- Tankyrases/chemistry
- Tankyrases/metabolism
- Ubiquitination
- Wnt Signaling Pathway*
- Zebrafish
- PubMed
- 32698014 Full text @ Cell Rep.
Citation
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. 32:107922.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping