title: Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding.
abstract: The myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF)-mediated gene expression. Activation of MRTF-A occurs in response to alterations in actin dynamics and critically requires the dissociation of repressive G-actin-MRTF-A complexes. However, the mechanism leading to the release of MRTF-A remains unclear. Here we show that WH2 domains compete directly with MRTF-A for actin binding. Actin nucleation-promoting factors, such as N-WASP and WAVE2, as well as isolated WH2 domains, including those of Spire2 and Cobl, activate MRTF-A independently of changes in actin dynamics. Simultaneous inhibition of Arp2-Arp3 or mutation of the CA region only partially reduces MRTF-A activation by N-WASP and WAVE2. Recombinant WH2 domains and the RPEL domain of MRTF-A bind mutually exclusively to cellular and purified G-actin in vitro The competition by different WH2 domains correlates with MRTF-SRF activation. Following serum stimulation, nonpolymerizable actin dissociates from MRTF-A, and de novo formation of the G-actin-RPEL complex is impaired by a transferable factor. Our work demonstrates that WH2 domains activate MRTF-A and contribute to target gene regulation by a competitive mechanism, independently of their role in actin filament formation.
authors.affiliation: Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Weissbach
authors.affiliation: Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Schikora
authors.affiliation: Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute for Biochemistry I, Medical Faculty, Friedrich Schiller University Jena, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kessels
authors.affiliation: Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany guido.posern@uk-halle.de.
authors.forename: Guido
authors.initials: G
authors.lastname: Posern
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D000072417:Protein Domains; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000199:Actins; C511173:Mrtfa protein, mouse; D011506:Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators