Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Cell Rep. 2020 Jul 21;32(3):107922. doi: 10.1016/j.celrep.2020.107922.
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.
Wnt/β-catenin 信号的时空控制对于机体发育和内稳态至关重要。多聚（ADP-核糖）聚合酶 Tankyrase（TNKS1）通过 PARylation 介导的 β-catenin 破坏复合物成分 AXIN1 的降解来促进 Wnt/β-catenin 信号。尽管 Wnt/β-catenin 是一种局限于特定组织的信号通路，但调控 TNKS1 的组织特异性因子尚不清楚。在这里，我们报告前列腺相关基因 4（PAGE4）作为一种组织特异性 TNKS1 抑制剂，可在人细胞、斑马鱼和小鼠中强烈抑制经典的 Wnt/β-catenin 信号。结构和生化研究表明，PAGE4 作为一种有效的底物诱饵，可强力占据 TNKS1 的底物结合位点，防止 AXIN1 的 PARylation 和降解。一致地，在小鼠中转基因表达 PAGE4 可模拟 TNKS1 敲除。生理上，PAGE4 选择性地在基质前列腺成纤维细胞中表达，并通过抑制自分泌信号来建立适当的 Wnt/β-catenin 信号龛。我们的研究结果揭示了一种非典型的 TNKS1 抑制机制，该机制可用于建立 Wnt/β-catenin 途径的组织特异性控制。
