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

Yuji Kubota, Yuko Fujioka, Ashwini Patil, Yusuke Takagi, Daisuke Matsubara, Masatomi Iijima, Isao Momose, Ryosuke Naka, Kenta Nakai, Nobuo N. Noda and Mutsuhiro Takekawa ()
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Yuji Kubota: The University of Tokyo
Yuko Fujioka: Microbial Chemistry Research Foundation
Ashwini Patil: The University of Tokyo
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
Mutsuhiro Takekawa: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31690-w

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