Phosphorylation acts positively and negatively to regulate MRTF-A subcellular localisation and activity
journal contributionposted on 07.09.2020, 11:37 by Richard Panayiotou, Francesc Miralles, Rafal Pawlowski, Jessica Diring, Helen R Flynn, Mark Skehel, Richard Treisman
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.
NESRPELSRFactincell biologychromosomesgeneshumanmousesignal transductiontranscriptionActinsAnimalsCell LineMicePhosphorylationProtein Processing, Post-TranslationalTrans-ActivatorsTranscription, Geneticrho GTP-Binding ProteinsTreisman FC001190PRTPC-ackHTS-ackGEP-ack0601 Biochemistry and Cell Biology