Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity.
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.
Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom.
Richard
R
Panayiotou
Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom.
Francesc
0000-0003-3069-2725
F
Miralles
Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom.
Rafal
R
Pawlowski
Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom.
Jessica
J
Diring
Mass Spectrometry Science Technology Platform, Francis Crick Institute, London, United Kingdom.
Helen R
0000-0001-7002-9130
HR
Flynn
Mass Spectrometry Science Technology Platform, Francis Crick Institute, London, United Kingdom.
Mark
M
Skehel
Signaling and Transcription Group, Francis Crick Institute, London, United Kingdom.
Richard
0000-0002-9658-0067
R
Treisman
D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; C511173:Mrtfa protein, mouse; D015534:Trans-Activators; D020741:rho GTP-Binding Proteins
NES; RPEL; SRF; actin; cell biology; chromosomes; genes; human; mouse; signal transduction; transcription