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

Christopher A. Waudby, Saul Alvarez-Teijeiro, E. Josue Ruiz, Simon Suppinger, Nikos Pinotsis, Paul R. Brown, Axel Behrens, John Christodoulou () and Anastasia Mylona ()
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Christopher A. Waudby: University College London
Saul Alvarez-Teijeiro: University of London
E. Josue Ruiz: Institute of Cancer Research
Simon Suppinger: University of London
Nikos Pinotsis: University of London
Paul R. Brown: King’s College
Axel Behrens: Institute of Cancer Research
John Christodoulou: University College London
Anastasia Mylona: University of London

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33866-w

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