Cu/Zn Superoxide Dismutase (Sod1) regulates the canonical Wnt signaling pathway

Cu/Zn Superoxide Dismutase (Sod1) catalyzes the disproportionation of cytotoxic superoxide radicals (O₂^•-) into oxygen (O₂) and hydrogen peroxide (H₂O₂), a key signaling molecule. In Saccharomyces cerevisiae, we previously discovered that Sod1 participates in an H₂O₂-mediated redox signaling circuit that links nutrient availability to the control of energy metabolism. In response to glucose and O₂, Sod1-derived H₂O₂ stabilizes a pair of conserved plasma membrane kinases - yeast casein kinase 1 and 2 (Yck1/2) - that signal glycolytic growth and the repression of respiration. The Yck1/2 homolog in humans, casein kinase 1-γ (CK1γ), is an integral component of the Wingless and Int-1 (Wnt) signaling pathway, which is essential for regulating cell fate and proliferation in early development and adult tissue and is dysregulated in many cancers. Herein, we establish the conservation of the SOD1/YCK1 redox signaling axis in humans by finding that SOD1 regulates CK1γ expression in human embryonic kidney 293 (HEK293) cells and is required for canonical Wnt signaling and Wnt-dependent cell proliferation.