Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation
journal contributionposted on 07.09.2020, 11:23 by Anastasia Mylona, Francois-Xavier Theillet, Charles Foster, Tammy M Cheng, Francesc Miralles, Paul A Bates, Philipp Selenko, Richard Treisman
Multisite phosphorylation regulates many transcription factors, including the serum response factor partner Elk-1. Phosphorylation of the transcriptional activation domain (TAD) of Elk-1 by the protein kinase ERK at multiple sites potentiates recruitment of the Mediator transcriptional coactivator complex and transcriptional activation, but the roles of individual phosphorylation events had remained unclear. Using time-resolved nuclear magnetic resonance spectroscopy, we found that ERK2 phosphorylation proceeds at markedly different rates at eight TAD sites in vitro, which we classified as fast, intermediate, and slow. Mutagenesis experiments showed that phosphorylation of fast and intermediate sites promoted Mediator interaction and transcriptional activation, whereas modification of slow sites counteracted both functions, thereby limiting Elk-1 output. Progressive Elk-1 phosphorylation thus ensures a self-limiting response to ERK activation, which occurs independently of antagonizing phosphatase activity.
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AnimalsEnzyme ActivationGene Expression RegulationHumansMAP Kinase Signaling SystemMiceMitogen-Activated Protein Kinase 1MutagenesisNuclear Magnetic Resonance, BiomolecularPhosphorylationProtein DomainsSerum Response Factorets-Domain Protein Elk-1Treisman FC001190BatesGEP-ackFC-ackGeneral Science & Technology