An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment.
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ICR Authors
Authors
Waudby, CA
Alvarez-Teijeiro, S
Josue Ruiz, E
Suppinger, S
Pinotsis, N
Brown, PR
Behrens, A
Christodoulou, J
Mylona, A
Alvarez-Teijeiro, S
Josue Ruiz, E
Suppinger, S
Pinotsis, N
Brown, PR
Behrens, A
Christodoulou, J
Mylona, A
Document Type
Journal Article
Date
2022-10-17
Date Accepted
2022-10-05
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.
Citation
Nature Communications, 2022, 13 (1), pp. 6133 -
Source Title
Nature Communications
Publisher
Springer Science and Business Media LLC
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Convergence SC Management