https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
https://ror.org/052gg0110 Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Life Sci Alliance. 2024 Mar 7;7(5). doi: 10.26508/lsa.202302245. Print 2024 May.
KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute to ∼30% of human solid tumours, including lung adenocarcinoma, pancreatic, and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. However, the precise signalling cascades these mutations affect are poorly understood. Here, APEX2 proximity labelling was used to profile the molecular environment of WT, G12D, G13D, and Q61H-activating KRAS mutants under starvation and stimulation conditions. Through quantitative proteomics, we demonstrate the presence of known KRAS interactors, including ARAF and LZTR1, which are differentially captured by WT and KRAS mutants. Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.
KRAS 是一种原癌基因，编码一种小分子 GTPase。突变约占人类实体肿瘤的 30%，包括肺腺癌、胰腺癌和结直肠癌。大多数 KRAS 激活突变干扰 GTP 水解，这对其作为分子开关的作用至关重要，导致其分子环境和致癌信号发生改变。然而，这些突变影响的确切信号级联仍知之甚少。在这里，APEX2 邻近标记法用于在饥饿和刺激条件下对 WT、G12D、G13D 和 Q61H 激活 KRAS 突变体的分子环境进行分析。通过定量蛋白质组学，我们证明了已知的 KRAS 相互作用物的存在，包括 ARAF 和 LZTR1，它们被 WT 和 KRAS 突变体以不同的方式捕获。值得注意的是，KRAS 突变 G12D、G13D 和 Q61H 使其与 LZTR1 的关联丧失，从而影响其周转率。阐明 LZTR1 介导的 KRAS 蛋白水平调节对癌症的影响可能为针对 KRAS 驱动的恶性肿瘤的治疗策略提供新的见解。
