TY - JOUR TI - Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity AU - Panayiotou, Richard AU - Miralles, Francesc AU - Pawlowski, Rafal AU - Diring, Jessica AU - Flynn, Helen R AU - Skehel, Mark AU - Treisman, Richard A2 - Davis, Roger J VL - 5 PY - 2016 DA - 2016/06/15 SP - e15460 C1 - eLife 2016;5:e15460 DO - 10.7554/eLife.15460 UR - https://doi.org/10.7554/eLife.15460 AB - 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. KW - transcription KW - signal transduction KW - actin KW - SRF KW - NES KW - RPEL JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -