The Francis Crick Institute
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An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment.

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journal contribution
posted on 2022-10-26, 08:27 authored by Christopher A Waudby, Saul Alvarez-Teijeiro, E Josue Ruiz, Simon Suppinger, Nikos Pinotsis, Paul R Brown, Axel Behrens, John Christodoulou, Anastasia Mylona
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.


Crick (Grant ID: 10029, Grant title: Frenkiel FC001029) Crick (Grant ID: 10039, Grant title: Behrens FC001039)