FNDC1 Competitively Binds Gβ2 to Suppress the β-Catenin Destruction Complex and Enhance Wnt Signaling Pathway Activation

Abstract

Background: Elevated FNDC1 expression in gastric cancer (GC) cells activates the Wnt/β-catenin pathway, contributing to their malignant traits. However, the exact mechanism governing this process remains unclear. Methods: Bioinformatics analyses were used to identify the expression of FDNC1 in pan-cancer, its correlation with clinical outcomes, and biological functions in GC. Co-immunoprecipitation assays and western blot elucidate the interaction between FDNC1 and Gβ2/Gγ2 and the expression of Axin1, GSK3β, APC, and Dvl. The specific binding sites of FNDC1 and Gβ2 were explored by co-immunoprecipitation. Results: FNDC1 was highly expressed in GC tissue, and its expression level is positively correlated with poor prognosis of GC. Functional enrichment analysis shows that FNDC1-related genes may participate in regulating the Wnt signaling pathway. In vitro assays prove that FNDC1 competitively binds to the Gβ2 protein. This binding caused Dvl to separate from Gβγ. Subsequently, Dvl was released and recruited Axin1, facilitating the degradation of Axin1 and activating the Wnt/β-catenin signaling pathway. We further identified the WD5 amino acid segment (residues 224-254) as the specific binding region of FNDC1 on Gβ2. Discussion: This study reveals a novel mechanism where FNDC1 competitively binds Gβ2, inhibiting β-catenin degradation and enhancing the Wnt/β-catenin signaling pathway.