Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth
| Autor: | Cezanne Miete, Gonzalo P. Solis, Alexey Koval, Martina Brückner, Vladimir L. Katanaev, Jürgen Behrens, Dominic B. Bernkopf |
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| Rok vydání: | 2021 |
| Předmět: |
Cell Proliferation / genetics
Xenograft Model Antitumor Assays / methods Science General Physics and Astronomy Mice Nude Axin Protein / metabolism General Biochemistry Genetics and Molecular Biology Colorectal Neoplasms / pathology Guanabenz / pharmacology Colorectal Neoplasms / genetics Axin Protein Wnt Signaling Pathway / genetics Cell Line Tumor Adrenergic alpha-2 Receptor Agonists Animals Humans ddc:610 ddc:612 neoplasms Wnt Signaling Pathway beta Catenin Cell Proliferation Axin Protein / genetics Mice Inbred BALB C Multidisciplinary Guanabenz General Chemistry Xenograft Model Antitumor Assays GTP-Binding Protein alpha Subunit Gi2/metabolism digestive system diseases Gene Expression Regulation Neoplastic Mice Inbred C57BL Beta Catenin / genetics HEK293 Cells Mutation Wnt Signaling Pathway / drug effects Adrenergic alpha-2 Receptor Agonists/pharmacology Cell Proliferation / drug effects Female GTP-Binding Protein alpha Subunit Gi2 Colorectal Neoplasms / metabolism Beta Catenin / metabolism Colorectal Neoplasms GTP-Binding Protein alpha Subunit Gi2 / genetics |
| Zdroj: | Nature Communications, Vol 13, Iss 1, Pp 1-16 (2022) Nature communications, Vol. 13, No 1 (2022) P. 674 |
| ISSN: | 2041-1723 |
| Popis: | Conductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/β-catenin signaling pathway. Accumulation of scaffold proteins in condensates frequently increases their activity, but whether condensation contributes to Wnt pathway inhibition by conductin remains unclear. Here, we show that the Gαi2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated β-catenin degradation. Consistently, transient Gαi2 expression inhibited, whereas knockdown activated Wnt signaling via conductin. Colorectal cancers appear to evade Gαi2-induced Wnt pathway suppression by decreased Gαi2 expression and inactivating mutations, associated with shorter patient survival. Notably, the Gαi2-activating drug guanabenz inhibited Wnt signaling via conductin, consequently reducing colorectal cancer growth in vitro and in mouse models. In summary, we demonstrate Wnt pathway inhibition via Gαi2-triggered conductin condensation, suggesting a tumor suppressor function for Gαi2 in colorectal cancer, and pointing to the FDA-approved drug guanabenz for targeted cancer therapy. |
| Databáze: | OpenAIRE |
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