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An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment

Author

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  • Christopher A. Waudby

    (University College London
    University College London)

  • Saul Alvarez-Teijeiro

    (University of London
    Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
    CIBERONC, Instituto de Salud Carlos III)

  • E. Josue Ruiz

    (Institute of Cancer Research)

  • Simon Suppinger

    (University of London
    Friedrich Miescher Institute for Biomedical Research (FMI))

  • Nikos Pinotsis

    (University of London)

  • Paul R. Brown

    (King’s College)

  • Axel Behrens

    (Institute of Cancer Research
    Imperial College
    Imperial College)

  • John Christodoulou

    (University College London
    University of London)

  • Anastasia Mylona

    (University of London
    Imperial College)

Abstract

Protein phosphorylation is a major regulatory mechanism of cellular signalling. The c-JUN proto-oncoprotein is phosphorylated at four residues within its transactivation domain (TAD) by the JNK family kinases, but the functional significance of c-JUN multisite phosphorylation has remained elusive. Here we show that c-JUN phosphorylation by JNK exhibits defined temporal kinetics, with serine63 and serine73 being phosphorylated more rapidly than threonine91 and threonine93. We identify the positioning of the phosphorylation sites relative to the kinase docking motif, and their primary sequence, as the main factors controlling phosphorylation kinetics. Functional analysis reveals three c-JUN phosphorylation states: unphosphorylated c-JUN recruits the MBD3 repressor, serine63/73 doubly-phosphorylated c-JUN binds to the TCF4 co-activator, whereas the fully phosphorylated form disfavours TCF4 binding attenuating JNK signalling. Thus, c-JUN phosphorylation encodes multiple functional states that drive a complex signalling response from a single JNK input.

Suggested Citation

  • Christopher A. Waudby & Saul Alvarez-Teijeiro & E. Josue Ruiz & Simon Suppinger & Nikos Pinotsis & Paul R. Brown & Axel Behrens & John Christodoulou & Anastasia Mylona, 2022. "An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33866-w
    DOI: 10.1038/s41467-022-33866-w
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    References listed on IDEAS

    as
    1. Piers Nash & Xiaojing Tang & Stephen Orlicky & Qinghua Chen & Frank B. Gertler & Michael D. Mendenhall & Frank Sicheri & Tony Pawson & Mike Tyers, 2001. "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication," Nature, Nature, vol. 414(6863), pages 514-521, November.
    2. Abdolrahman S. Nateri & Bradley Spencer-Dene & Axel Behrens, 2005. "Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development," Nature, Nature, vol. 437(7056), pages 281-285, September.
    3. Cristina Aguilera & Kentaro Nakagawa & Rocio Sancho & Atanu Chakraborty & Brian Hendrich & Axel Behrens, 2011. "c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex," Nature, Nature, vol. 469(7329), pages 231-235, January.
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