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Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex.
Damianou, Andreas; Liang, Zhu; Lassen, Frederik; Vendrell, Iolanda; Vere, George; Hester, Svenja; Charles, Philip D; Pinto-Fernandez, Adan; Santos, Alberto; Fischer, Roman; Kessler, Benedikt M.
Afiliação
  • Damianou A; https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK andreas.damianou@ndm.ox.ac.uk.
  • Liang Z; https://ror.org/052gg0110 Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Lassen F; https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Vendrell I; https://ror.org/052gg0110 Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Vere G; https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Hester S; https://ror.org/052gg0110 Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Charles PD; https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Pinto-Fernandez A; https://ror.org/052gg0110 Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Fischer R; https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Kessler BM; https://ror.org/052gg0110 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Life Sci Alliance ; 7(5)2024 May.
Article em En | MEDLINE | ID: mdl-38453365
ABSTRACT
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Proteínas Proto-Oncogênicas p21(ras) / Ubiquitina-Proteína Ligases Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Proteínas Proto-Oncogênicas p21(ras) / Ubiquitina-Proteína Ligases Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article