ReportSignal Transduction

Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation

See allHide authors and affiliations

Science  14 Oct 2016:
Vol. 354, Issue 6309, pp. 233-237
DOI: 10.1126/science.aad1872

You are currently viewing the abstract.

View Full Text

A function for multisite phosphorylation

Many transcription factors are regulated by phosphorylation on multiple residues. Mylona et al. analyzed multisite phosphorylation in the transcription factor Elk-1 and showed that it may protect against excessive activation (see the Perspective by Whitmarsh and Davis). Phosphorylation by the kinase ERK2 occurred at eight sites, but the sites were phosphorylated at different rates. Those that were phosphorylated more quickly promoted transcriptional activation. Those that were phosphorylated more slowly dampened excessive activation by ERK2s without needing a phosphatase or any other negative regulatory component.

Science, this issue p. 233; see also p. 179

Abstract

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.

View Full Text