2. Academic Validation
  3. ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1

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

  • Mol Cell. 2022 Jul 7;82(13):2443-2457.e7. doi: 10.1016/j.molcel.2022.04.034.
Wenjing Su 1,  Radha Mukherjee 1,  Rona Yaeger 2,  Jieun Son 3,  Jianing Xu 1,  Na Na 1,  Neilawattie Merna Timaul 1,  Jaclyn Hechtman 4,  Viktoriya Paroder 5,  Mika Lin 3,  Marissa Mattar 1,  Juan Qiu 1,  Qing Chang 1,  Huiyong Zhao 1,  Jonathan Zhang 1,  Megan Little 1,  Yuta Adachi 6,  Sae-Won Han 7,  Barry S Taylor 8,  Hiromichi Ebi 9,  Omar Abdel-Wahab 10,  Elisa de Stanchina 1,  Charles M Rudin 2,  Pasi A Jänne 3,  Frank McCormick 11,  Zhan Yao 12,  Neal Rosen 13
Affiliations

Affiliations

  • 1 Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 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.
  • 4 Department of Pathology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Department of Radiology, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6 Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
  • 7 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.
  • 8 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.
  • 9 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.
  • 10 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.
  • 11 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.
  • 12 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: [email protected].
  • 13 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: [email protected].
PMID: 35613620 DOI: 10.1016/j.molcel.2022.04.034
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.

Keywords

ARAF; ERK signaling; NF1; RAS-GTP; drug sensitivity; receptor tyrosine kinase inhibitor.

Figures
Products