Song Jiangwei, Wang Busong, Zou Mingjie, Zhou Haiyuan, Ding Yibing, Ren Wei, Fang Lei, Zhang Jingzi
Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210093, China.
State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center, Medical School of Nanjing University, Nanjing 210029, China.
Biology (Basel). 2025 Apr 26;14(5):477. doi: 10.3390/biology14050477.
KRAS mutations are major drivers of human cancers, yet how distinct mutations rewire protein interactions and metabolic pathways to promote tumorigenesis remains poorly understood. To address this, we systematically mapped the protein interaction networks of wild-type KRAS and three high-frequency oncogenic mutants (G12C, G12D, and G12V) using TurboID proximity labeling coupled with quantitative proteomics. Bioinformatic analysis revealed mutant-specific binding partners and metabolic pathway alterations, including significant enrichment in insulin signaling, reactive oxygen species regulation, and glucose/lipid metabolism. These changes collectively drive tumor proliferation and immune evasion. Comparative analysis identified shared interactome shifts across all mutants: reduced binding to LZTR1, an adaptor for KRAS degradation, and enhanced recruitment of LAMTOR1, a regulator of mTORC1-mediated growth signaling. Our multi-dimensional profiling establishes the first comprehensive map of KRAS-mutant interactomes and links specific mutations to metabolic reprogramming. These findings provide mechanistic insights into KRAS-driven malignancy and highlight LZTR1 and LAMTOR1 as potential therapeutic targets. The study further lays a foundation for developing mutation-specific strategies to counteract KRAS oncogenic signaling.
KRAS突变是人类癌症的主要驱动因素，然而，不同的突变如何重塑蛋白质相互作用和代谢途径以促进肿瘤发生，目前仍知之甚少。为了解决这个问题，我们使用TurboID邻近标记结合定量蛋白质组学，系统地绘制了野生型KRAS和三种高频致癌突变体（G12C、G12D和G12V）的蛋白质相互作用网络。生物信息学分析揭示了突变体特异性的结合伙伴和代谢途径改变，包括胰岛素信号传导、活性氧调节以及葡萄糖/脂质代谢的显著富集。这些变化共同驱动肿瘤增殖和免疫逃逸。比较分析确定了所有突变体共有的相互作用组变化：与KRAS降解衔接蛋白LZTR1的结合减少，以及mTORC1介导的生长信号调节因子LAMTOR1的募集增加。我们的多维分析建立了首张KRAS突变体相互作用组的全面图谱，并将特定突变与代谢重编程联系起来。这些发现为KRAS驱动的恶性肿瘤提供了机制性见解，并突出了LZTR1和LAMTOR1作为潜在治疗靶点。该研究进一步为开发对抗KRAS致癌信号的突变特异性策略奠定了基础。
