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ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1

  1. Author:
    Su, Wenjing
    Mukherjee, Radha
    Yaeger, Rona
    Son, Jieun
    Xu, Jianing
    Na, Na
    Merna Timaul, Neilawattie
    Hechtman, Jaclyn
    Paroder, Viktoriya
    Lin, Mika
    Mattar, Marissa
    Qiu, Juan
    Chang, Qing
    Zhao, Huiyong
    Zhang, Jonathan
    Little, Megan
    Adachi, Yuta
    Han, Sae-Won
    Taylor, Barry S
    Ebi, Hiromichi
    Abdel-Wahab, Omar
    de Stanchina, Elisa
    Rudin, Charles M
    Jänne, Pasi A
    McCormick, Frank
    Yao, Zhan
    Rosen, Neal

  2. Author Address

    Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA., Department of Pathology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Radiology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan., UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, South Korea., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA; Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Discovery and Applied Genomics, Loxo Oncology at Lilly, Stamford, CT 06901, USA., Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan; Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, 466-8650, Japan., Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA., UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21701, USA., Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Mechanistic Biology, Loxo Oncology at Lilly, New York, NY 10016, USA. Electronic address: zyao@loxooncology.com., Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rosenn@mskcc.org.,
    1. Year: 2022
    2. Date: May 14
    3. Epub Date: 2022 05 14
  2. Journal: Molecular Cell
  4. Type of Article: Article
  1. Abstract:

    RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.molcel.2022.04.034
  3. PMID: 35613620
  4. PII : S1097-2765(22)00434-8

Library Notes

  1. Fiscal Year: FY2021-2022
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