An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy

Abstract

The paralogous scaffold proteins axin and conductin/axin2 are key factors in the negative regulation of the Wnt pathway transcription factor β-catenin, thereby representing interesting targets for signaling regulation. Polymerization of axin proteins is essential for their activity in suppressing Wnt/β-catenin signaling. Notably, conductin shows less polymerization and lower activity than axin. By domain swapping between axin and conductin we here identify an aggregation site in the conductin RGS domain which prevents conductin polymerization. Induction of conductin polymerization by point mutations of this aggregon results in enhanced inhibition of Wnt/β-catenin signaling. Importantly, we identify a short peptide which induces conductin polymerization via masking the aggregon, thereby enhancing β-catenin degradation, inhibiting β-catenin-dependent transcription and repressing growth of colorectal cancer cells. Our study reveals a mechanism for regulating signaling pathways via the polymerization status of scaffold proteins and suggests a strategy for targeted colorectal cancer therapy.

Targeting the Wnt/β-catenin signaling pathway in cancer

“…Scaffolding protein AXIN is the rate-limiting component of the β-catenin destruction complex, which are constantly surveyed and regulated by tankyrases [56][57][58]. Tankyrases belong to the Poly (ADP-ribose) polymerases (PARPs) family, regulating the stability of AXIN1 and AXIN2 through directing AXIN ubiquitylation by RNF146 and proteasomal degradation [59,60].…”

Wnt/β-catenin signaling in cancers and targeted therapies

“… 153 , 154 Controlling Axin polymerization may be a potential therapeutic choice to suppress cancer development. 154 , 155 Mutations of AxinCR were reported to accelerate the tumorigenesis in the following cancers: HCC, colorectal adenomas, ovarian carcinomas, lung carcinomas, and sporadic medulloblastomas. Therefore, erasing or eliminating the mutations of Axin could a promising method to combat diverse cancers.…”

“… 158 , 159 Axin2 can partially compensate for the functional impairment caused by Axin1 mutation. 155 , 158 , 160 Axin2 dysfunction was associated with a variety of tumors, including endometrial cancer, 161 CRC, 162 – 165 lung cancer, 166 , 167 and breast cancer. 168 – 170 In these cancers, Axin2 performed suppressive roles by mainly constraining the level of β-catenin.…”

Upregulation of Parkin Accelerates Osteoblastic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells and Bone Regeneration by Enhancing Autophagy and β-Catenin Signaling

“…In the Wnt inactive state, cytosolic β-catenin is phosphorylated and degraded ( Sakanaka, 2002 ) whereas in the Wnt active state, the Wnt ligand prevents β-catenin phosphorylation and non-phosphorylated β-catenin transduces cytosolic signals to the nucleus and triggers transcription of target genes ( Sakanaka, 2002 ; Valenta et al, 2012 ; Marchetti, 2018 ). Axin2 negatively regulates β-catenin and is a target of Wnt/β-catenin signaling ( Bernkopf et al, 2019 ). LEF1, binding to Wnt response elements to provide docking sites for β-catenin is a Wnt signaling pathway marker ( Zhang M. et al, 2018 ).…”