Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

Andrew M. Kidger, Linda K. Rushworth, Julia Stellzig, Jane Davidson, Christopher J. Bryant, Cassidy Bayley, Edward Caddye, Tim Rogers, Stephen M. Keyse (Lead / Corresponding author), Christopher J. Caunt (Lead / Corresponding author)

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    Abstract

    Deregulated ERK signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that while the MKP, DUSP5, both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERKmediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAFV600E, a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAFV600E-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate.
    Original languageEnglish
    Pages (from-to)E317-E326
    Number of pages10
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume114
    Issue number3
    Early online date4 Jan 2017
    DOIs
    Publication statusPublished - 17 Jan 2017

    Keywords

    • ERK
    • MAPK
    • MKP
    • DUSP
    • Signalling

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