Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity
Open accessAbstract
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 the regulation of MRTF-A.
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All these signals (actin polymerisation, contractibility or SRC/ERK/PI3K pathways) are upstream of the activation of MRTcoF.
“It seems that a full inhibition may be performed in parallel with the blockage of actin polymerisation, contractibility or SRC/ERK/PI3K pathways (latrunculin B, blebbistatin and dasatinib/U0126/LY294002, respectively) because all these signals are upstream of the activation of MRTcoF [22, 70].”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [70]
The Introduction and the Discussion section “G-actin binding controls MRTF-A phosphorylation” link actin dynamics to MRTF-A regulation, and the Results section “Phorbol esters act positively and negatively to regulate MRTF-A” reports ERK-dependent MRTF-A activation. Our copy does not establish contractility, SRC, or PI3K as upstream activators of MRTF-A, so it does not support the claim that all the listed signals are upstream. (LLM, conf=0.87)
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- Authors
- Panayiotou, R., Miralles, F., Pawlowski, R., Diring, J., Flynn, H. R., Skehel, M., & Treisman, R.
- Affiliations
- The Francis Crick Institute (GB)
- Corresponding author
- Treisman, Richard
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-06-15
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4963197
- OpenAlex
- W2420944975
- Cited by
- 79
- References
- 1
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 18 · 2021: 14 · 2020: 8 · 2019: 8 · 2018: 7 · 2017: 8 · 2016: 2
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK (Crick Core Funding FC001-190, LRI Core Funding to 2015)
- Medical Research Council (Crick Core Funding FC001-190)
- Wellcome Trust (Crick Core Funding FC001-190)
- European Research Council (Advanced Grant 268690)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- MRTF-A, MRTF, phosphorylation, nuclear export, nuclear import, nuclear actin, Rho GTPase signaling, ERK signaling, nuclear export sequence, CRM1, SRF, subcellular localization
- MeSH terms
- Actins, Animals, Cell Line, Phosphorylation, Protein Processing, Post-Translational, Transcription, Genetic, Trans-Activators, rho GTP-Binding Proteins, Mice
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