{
  "abstract": "Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but their signaling in this context remains less well characterized than in carcinomas. Using multiomics screens in multiple myeloma, we sought to identify regulators of RAS activity. We found that the phosphatase PP1C dephosphorylated conserved RAS residue T148, permitting LZTR1-dependent proteasomal degradation. LZTR1 was ineffective against KRAS A146 gain-of-function mutations, which lie adjacent to T148 and are enriched in hematologic cancers, such as diffuse large B-cell lymphoma (DLBCL) and acute myeloid leukemia (AML). Remarkably, KRAS protein stability was 4-fold lower in hematologic versus carcinoma cells, revealing a unique therapeutic opportunity targeting RAS protein stability. PAK1 and PAK2 shielded RAS from LZTR1-dependent degradation by phosphorylating T148, and inhibiting PAK1/2 activity improved RAS-directed therapy. Collectively, these findings reveal a regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.\n\nSignificance:: We found that PP1C and PAK1/2 regulate RAS T148 phosphorylation, controlling LZTR1-mediated RAS degradation in multiple myeloma, DLBCL, and AML. PAK1/2 inhibition reduces RAS expression, enhancing the efficacy of RAS-directed therapies in multiple myeloma. Notably, KRAS A146 mutations, prevalent in blood cancers, can shield RAS from this degradation.\n\nSee related commentary by Boise, p. 860",
  "abstract_shown": true,
  "affiliations": [
    "Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.",
    "Protein Mass Spectrometry Group, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.",
    "Department of Medicine, Hematology and Oncology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.",
    "Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.",
    "German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Frankfurt am Main, Germany.",
    "German Cancer Research Center (DKFZ), Heidelberg, Germany.",
    "University Cancer Center (UCT), Frankfurt am Main, Germany.",
    "University of Maryland Greenbaum Comprehensive Cancer Center, Baltimore, Maryland.",
    "Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lin Zhang",
      "orcid": "0000-0003-2227-8014"
    },
    {
      "affs": [
        0
      ],
      "name": "Arnold Bolomsky",
      "orcid": "0000-0002-1585-5429"
    },
    {
      "affs": [
        0
      ],
      "name": "Omar S. Al-Odat",
      "orcid": "0000-0002-9563-6030"
    },
    {
      "affs": [
        0
      ],
      "name": "Callie K. VanWinkle",
      "orcid": "0000-0003-1957-9895"
    },
    {
      "affs": [
        0
      ],
      "name": "Aaliyah Battle",
      "orcid": "0009-0002-4303-9469"
    },
    {
      "affs": [
        0
      ],
      "name": "Papiya Chakraborty",
      "orcid": "0000-0002-7834-815X"
    },
    {
      "affs": [
        1
      ],
      "name": "Ronald J. Holewinski",
      "orcid": "0000-0002-3337-3984"
    },
    {
      "affs": [
        1
      ],
      "name": "Thorkell Andresson",
      "orcid": "0000-0002-9545-2450"
    },
    {
      "affs": [
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Björn Häupl",
      "orcid": "0009-0000-9445-9565"
    },
    {
      "affs": [
        2,
        3,
        4,
        5,
        6
      ],
      "name": "Thomas Oellerich",
      "orcid": "0000-0001-6570-6125"
    },
    {
      "affs": [
        0
      ],
      "name": "Elizabeth Hill",
      "orcid": "0009-0000-5152-5956"
    },
    {
      "affs": [
        7
      ],
      "name": "Mehmet Kocoglu",
      "orcid": "0000-0002-9888-5737"
    },
    {
      "affs": [
        8
      ],
      "name": "Qingcai Meng",
      "orcid": "0000-0001-5906-8366"
    },
    {
      "affs": [
        0
      ],
      "name": "James D. Phelan",
      "orcid": "0000-0001-8950-2485"
    },
    {
      "affs": [
        0
      ],
      "name": "Jagan Muppidi",
      "orcid": "0000-0002-2639-4226"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryan M. Young",
      "orcid": "0000-0003-0706-8019"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/epxvrfyd53yfy.bib",
  "cited_by": 1,
  "doi": "10.1158/2643-3230.bcd-26-0028",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13728799/",
  "id": "epxvrfyd53yfy",
  "issns": [
    "2643-3230",
    "2643-3249"
  ],
  "landing_url": "https://doi.org/10.1158/2643-3230.bcd-26-0028",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Biochemistry"
    ],
    [
      "heading",
      "Functional Genomics"
    ],
    [
      "heading",
      "Genome Biology"
    ],
    [
      "heading",
      "Hematological Cancers"
    ],
    [
      "heading",
      "Kras"
    ],
    [
      "heading",
      "Oncogenes & Tumor Suppressors"
    ],
    [
      "heading",
      "Protein/Protein Interactions"
    ],
    [
      "heading",
      "Proteomics"
    ],
    [
      "heading",
      "Research Articles"
    ],
    [
      "openalex",
      "1312|Protein Kinase Regulation and GTPase Signaling"
    ]
  ],
  "openalex": "W7118582065",
  "pdf_url": null,
  "pmcid": "PMC13728799",
  "pmid": "42671911",
  "published": "2026-08-31",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/epxvrfyd53yfy.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:21:42Z",
      "native_id": "PMC13728799",
      "source": "pmc",
      "url": "https://doi.org/10.1158/2643-3230.bcd-26-0028"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "heading:Proteomics",
      "subfield": "proteomics-metabolomics"
    }
  ],
  "title": "Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation",
  "title_text": "Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:21:42Z",
  "url": "https://research.draconitic.com/paper/epxvrfyd53yfy",
  "venue": "Blood Cancer Discovery",
  "versions": []
}