Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity

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Abstract

The myocardin-related transcription factors (MRTF-A and MRTF-B) regulate cytoskeletal genes through their partner transcription factor SRF. The MRTFs bind G-actin, and signal-regulated changes in cellular G-actin concentration control their nuclear accumulation. The MRTFs also undergo Rho- and ERK-dependent phosphorylation, but the function of MRTF phosphorylation, and the elements and signals involved in MRTF-A nuclear export are largely unexplored. We show that Rho-dependent MRTF-A phosphorylation reflects relief from an inhibitory function of nuclear actin. We map multiple sites of serum-induced phosphorylation, most of which are S/T-P motifs, and show that S/T-P phosphorylation is required for transcriptional activation. ERK-mediated S98 phosphorylation inhibits assembly of G-actin complexes on the MRTF-A regulatory RPEL domain, promoting nuclear import. In contrast, S33 phosphorylation potentiates the activity of an autonomous Crm1-dependent N-terminal NES, which cooperates with five other NES elements to exclude MRTF-A from the nucleus. Phosphorylation thus plays positive and negative roles in regulation of MRTF-A.

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Richard Panayiotou

Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Francesc Miralles

Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Rafal Pawlowski

Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Jessica Diring

Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Helen R Flynn

Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Mark Skehel

Mass Spectrometry science technology platform, Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Richard Treisman

Signalling and Transcription Group, Francis Crick Institute, London, United Kingdom

For correspondence
Richard.Treisman@Crick.ac.uk

Competing interests
The authors declare that no competing interests exist.

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