An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment.
Date
2022-10-17ICR Author
Author
Waudby, CA
Alvarez-Teijeiro, S
Josue Ruiz, E
Suppinger, S
Pinotsis, N
Brown, PR
Behrens, A
Christodoulou, J
Mylona, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase 4
MAP Kinase Signaling System
Phosphorylation
Proto-Oncogene Proteins c-jun
Signal Transduction
Research team
Convergence SC Management
Language
eng
Date accepted
2022-10-05
License start date
2022-10-17
Citation
Nature Communications, 2022, 13 (1), pp. 6133 -
Publisher
Springer Science and Business Media LLC