Mapping the KRAS proteoform landscape in colorectal cancer identifies truncated KRAS4B that decreases MAPK signaling.

Autor:	Adams LM; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA., DeHart CJ; NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Drown BS; Department of Chemistry, Northwestern University, Evanston, Illinois, USA., Anderson LC; Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory, Tallahassee, Florida, USA., Bocik W; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA., Boja ES; Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland, USA., Hiltke TM; Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland, USA., Hendrickson CL; Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory, Tallahassee, Florida, USA., Rodriguez H; Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, Maryland, USA., Caldwell M; Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, USA; Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA., Vafabakhsh R; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA., Kelleher NL; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA; Department of Chemistry, Northwestern University, Evanston, Illinois, USA; Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, USA; Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA. Electronic address: n-kelleher@northwestern.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Jan; Vol. 299 (1), pp. 102768. Date of Electronic Publication: 2022 Dec 05.
DOI:	10.1016/j.jbc.2022.102768
Abstrakt:	The KRAS gene is one of the most frequently mutated oncogenes in human cancer and gives rise to two isoforms, KRAS4A and KRAS4B. KRAS post-translational modifications (PTMs) have the potential to influence downstream signaling. However, the relationship between KRAS PTMs and oncogenic mutations remains unclear, and the extent of isoform-specific modification is unknown. Here, we present the first top-down proteomics study evaluating both KRAS4A and KRAS4B, resulting in 39 completely characterized proteoforms across colorectal cancer cell lines and primary tumor samples. We determined which KRAS PTMs are present, along with their relative abundance, and that proteoforms of KRAS4A versus KRAS4B are differentially modified. Moreover, we identified a subset of KRAS4B proteoforms lacking the C185 residue and associated C-terminal PTMs. By confocal microscopy, we confirmed that this truncated GFP-KRAS4B C185 ∗ proteoform is unable to associate with the plasma membrane, resulting in a decrease in mitogen-activated protein kinase signaling pathway activation. Collectively, our study provides a reference set of functionally distinct KRAS proteoforms and the colorectal cancer contexts in which they are present. Competing Interests: Conflict of interest N. L. K. is involved in commercialization of proteomics software. All other authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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