Rahmat Muhammad Bakhait, Hussain Aashiq, Teh Yu Xuan, Dutta Bibek, Pundrik Sumedha, Kappei Dennis, Ito Yoshiaki
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Oncogene. 2025 Aug 19. doi: 10.1038/s41388-025-03512-y.
The scaffold protein IQGAP3 is highly upregulated in most epithelial cancers. While recent studies have highlighted its pivotal roles in cancer cell proliferation and metastasis, a deeper mechanistic understanding of IQGAP3 is currently lacking. We have here used TurboID to map IQGAP3 proximity partners and identified the Wnt signaling members Axin1 and CK1α as IQGAP3-interacting proteins. Our functional studies demonstrated that overexpression of IQGAP3 increases β-catenin levels, while IQGAP3 depletion reduces β-catenin levels in gastric cancer cells. Mechanistically, IQGAP3 disrupts Axin1-CK1α interaction, thereby inhibiting β-catenin phosphorylation and ultimately leading to its accumulation. Importantly, we discovered that IQGAP3 itself is regulated by Wnt signaling, suggesting its involvement in a positive feedback loop in Wnt/β-catenin signaling through interactions with Axin1 and CK1α. These findings identify IQGAP3 as a novel mediator of β-catenin stabilization and underscore its potential as a target for cancer therapy.
支架蛋白IQGAP3在大多数上皮癌中高度上调。虽然最近的研究强调了其在癌细胞增殖和转移中的关键作用，但目前对IQGAP3的机制理解仍不够深入。我们在此使用TurboID来绘制IQGAP3的邻近蛋白图谱，并鉴定出Wnt信号成员Axin1和CK1α为与IQGAP3相互作用的蛋白。我们的功能研究表明，IQGAP3的过表达会增加β-连环蛋白水平，而在胃癌细胞中敲低IQGAP3会降低β-连环蛋白水平。从机制上讲，IQGAP3破坏了Axin1-CK1α的相互作用，从而抑制β-连环蛋白的磷酸化并最终导致其积累。重要的是，我们发现IQGAP3本身受Wnt信号调控，这表明它通过与Axin1和CK1α相互作用参与Wnt/β-连环蛋白信号的正反馈回路。这些发现确定IQGAP3是β-连环蛋白稳定的新介质，并强调了其作为癌症治疗靶点的潜力。
