TY - JOUR T1 - Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS Mutations JF - bioRxiv DO - 10.1101/2021.11.23.469679 SP - 2021.11.23.469679 AU - Andreas Damianou AU - Zhu Liang AU - Frederik Lassen AU - George Vere AU - Svenja Hester AU - Philip D Charles AU - Adan Pinto-Fernandez AU - Alberto Santos-Delgado AU - Roman Fischer AU - Benedikt M Kessler Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/11/23/2021.11.23.469679.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -