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

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.

Article and author information

Author details

  1. Richard Panayiotou

    Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Francesc Miralles

    Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Rafal Pawlowski

    Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Jessica Diring

    Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Helen R Flynn

    Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Mark Skehel

    Mass Spectrometry science technology platform, Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. 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.

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: February 22, 2016
  2. Accepted: June 14, 2016
  3. Accepted Manuscript published: June 15, 2016 (version 1)
  4. Version of Record published: July 27, 2016 (version 2)

Copyright

© 2016, Panayiotou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Richard Panayiotou
  2. Francesc Miralles
  3. Rafal Pawlowski
  4. Jessica Diring
  5. Helen R Flynn
  6. Mark Skehel
  7. Richard Treisman
(2016)
Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity
eLife 5:e15460.
https://doi.org/10.7554/eLife.15460

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