Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS Mutations-猫眼课题宝

DOI：

10.1101/2021.11.23.469679

发表时间：

2021-11

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Andreas C. Damianou;Zhu Liang;Frederik H. Lassen;George Vere;Svenja S. Hester;P. Charles;Adán Pinto-Fernández;Alberto Santos-Delgado;R. Fischer;B. Kessler

KRAS是一种编码小GTP酶的原癌基因。突变导致高达30%的人类实体瘤，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，这对于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的改变。在此，使用APEX-2邻近标记来分析KRAS的野生型和G12 D、G13 D和Q61 H激活突变体在饥饿和刺激条件下的分子环境。我们通过定量蛋白质组学证明了KRAS的已知相互作用物的存在，包括a-RAF和LZTR 1，其在野生型和KRAS突变体中丰度不同。值得注意的是，KRAS突变G12 D、G13 D和Q61 H消除了与LZTR 1的关联。野生型KRAS和LZTR 1作为CUL 3泛素E3连接酶复合物的一部分，影响彼此的蛋白质稳定性，揭示了直接反馈环机制。KRAS突变断开了这种调节回路，从而有助于肿瘤发生。

KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute up 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. Here, APEX-2 proximity labelling was used to profile the molecular environment of wild type and G12D, G13D and Q61H activating mutants of KRAS under both, starvation and stimulation conditions. We demonstrate by quantitative proteomics the presence of known interactors of KRAS including a-RAF and LZTR1, which varied in abundance with wildtype and KRAS mutants. Notably, the KRAS mutations G12D, G13D and Q61H abrogate association with LZTR1. Wildtype KRAS and LZTR1, as part of the CUL3 ubiquitin E3 ligase complex, affect each other’s protein stability, revealing a direct feedback loop mechanism. KRAS mutations disconnect this regulatory circuit, thereby contributing to oncogenesis.

Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS Mutations

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