title: Filamin A interacts with the coactivator MKL1 to promote the activity of the transcription factor SRF and cell migration.
abstract: Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor (SRF) that promotes the expression of genes associated with cell proliferation, motility, adhesion, and differentiation-processes that also involve dynamic cytoskeletal changes in the cell. MKL1 is inactive when bound to monomeric globular actin (G-actin), but signals that activate the small guanosine triphosphatase RhoA cause actin polymerization and MKL1 dissociation from G-actin. We found a new mechanism of MKL1 activation that is mediated through its binding to filamin A (FLNA), a protein that binds filamentous actin (F-actin). The interaction of FLNA and MKL1 was required for the expression of MKL1 target genes in primary fibroblasts, melanoma, mammary and hepatocellular carcinoma cells. We identified the regions of interaction between MKL1 and FLNA, and cells expressing an MKL1 mutant that was unable to bind FLNA exhibited impaired cell migration and reduced expression of MKL1-SRF target genes. Induction and repression of MKL1-SRF target genes correlated with increased or decreased MKL1-FLNA interaction, respectively. Lysophosphatidic acid-induced RhoA activation in primary human fibroblasts promoted the association of endogenous MKL1 with FLNA, whereas exposure to an actin polymerization inhibitor dissociated MKL1 from FLNA and decreased MKL1-SRF target gene expression in melanoma cells. Thus, FLNA functions as a positive cellular transducer linking actin polymerization to MKL1-SRF activity, counteracting the known repressive complex of MKL1 and monomeric G-actin.
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kircher
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hermanns
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Nossek
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Maria Katharina
authors.initials: MK
authors.lastname: Drexler
authors.affiliation: Institute of Pharmacology, Biochemical-Pharmacological Center, University of Marburg, Marburg 35043, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grosse
authors.affiliation: Institute of Pharmacology and Toxicology, Technical University Munich, Munich 80802, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Institute of Pharmacology and Toxicology, Technical University Munich, Munich 80802, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sarikas
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Penkava
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Thera
authors.initials: T
authors.lastname: Lewis
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Prywes
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany. Comprehensive Pneumology Center Munich, German Center for Lung Research, Munich 81377, Germany. German Center for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich 80802, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.affiliation: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich 80336, Germany. susanne.muehlich@lrz.uni-muenchen.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Muehlich
mesh_terms: D016475:3T3 Cells; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D064448:Filamins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D026362:Serum Response Factor / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D000199:Actins; D064448:Filamins; C431575:MRTFA protein, human; D050505:Mutant Proteins; C476858:SRF protein, human; D026362:Serum Response Factor; D015534:Trans-Activators