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Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer

Author

Listed:
  • Yuji Kubota

    (The University of Tokyo)

  • Yuko Fujioka

    (Microbial Chemistry Research Foundation
    Hokkaido University)

  • Ashwini Patil

    (The University of Tokyo
    Combinatics Inc.)

  • Yusuke Takagi

    (The University of Tokyo)

  • Daisuke Matsubara

    (The University of Tokyo)

  • Masatomi Iijima

    (Microbial Chemistry Research Foundation)

  • Isao Momose

    (Microbial Chemistry Research Foundation)

  • Ryosuke Naka

    (The University of Tokyo)

  • Kenta Nakai

    (The University of Tokyo)

  • Nobuo N. Noda

    (Microbial Chemistry Research Foundation
    Hokkaido University)

  • Mutsuhiro Takekawa

    (The University of Tokyo)

Abstract

Point-mutations of MEK1, a central component of ERK signaling, are present in cancer and RASopathies, but their precise biological effects remain obscure. Here, we report a mutant MEK1 structure that uncovers the mechanisms underlying abnormal activities of cancer- and RASopathy-associated MEK1 mutants. These two classes of MEK1 mutations differentially impact on spatiotemporal dynamics of ERK signaling, cellular transcriptional programs, gene expression profiles, and consequent biological outcomes. By making use of such distinct characteristics of the MEK1 mutants, we identified cancer- and RASopathy-signature genes that may serve as diagnostic markers or therapeutic targets for these diseases. In particular, two AKT-inhibitor molecules, PHLDA1 and 2, are simultaneously upregulated by oncogenic ERK signaling, and mediate cancer-specific ERK-AKT crosstalk. The combined expression of PHLDA1/2 is critical to confer resistance to ERK pathway-targeted therapeutics on cancer cells. Finally, we propose a therapeutic strategy to overcome this drug resistance. Our data provide vital insights into the etiology, diagnosis, and therapeutic strategy of cancers and RASopathies.

Suggested Citation

  • Yuji Kubota & Yuko Fujioka & Ashwini Patil & Yusuke Takagi & Daisuke Matsubara & Masatomi Iijima & Isao Momose & Ryosuke Naka & Kenta Nakai & Nobuo N. Noda & Mutsuhiro Takekawa, 2022. "Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31690-w
    DOI: 10.1038/s41467-022-31690-w
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    References listed on IDEAS

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    1. Damian F. Brennan & Arvin C. Dar & Nicholas T. Hertz & William C. H. Chao & Alma L. Burlingame & Kevan M. Shokat & David Barford, 2011. "A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK," Nature, Nature, vol. 472(7343), pages 366-369, April.
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