Inhibition of arginyltransferase 1 induces transcriptional activity of myocardin-related transcription factor A (MRTF-A) and promotes directional migration.
Myocardin-related transcription factor A (MRTF-A/MAL/MKL1/BSAC) regulates the expression of serum-response factor (SRF)-dependent target genes in response to the Rho-actin signaling pathway. Overexpression or activation of MRTF-A affects shape, migration, and invasion of cells and contributes to human malignancies, including cancer. In this study, we report that inhibition of arginyltransferase 1 (ATE1), an enzyme mediating post-transcriptional protein arginylation, is sufficient to increase MRTF-A activity in MCF-7 human breast carcinoma cells independently of external growth factor stimuli. In addition, silencing or inhibiting ATE1 disrupted E-cadherin-mediated cell-cell contacts, enhanced formation of actin-rich protrusions, and increased the number of focal adhesions, subsequently leading to elevated chemotactic migration. Although arginylated actin did not differentially affect MRTF-A, a rapid loss of E-cadherin and F-actin reorganization preceded MRTF-A activation upon ATE1 inhibition. Conversely, ectopic ATE1 expression was sufficient to render MRTF-A inactive, both in resting cells and in cells with exogenously activated RhoA-actin pathways. In this study, we provide a critical link between protein arginylation and MRTF-A activity and place ATE1 upstream of myocardin-related transcription factor.
From the Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, 06114 Halle (Saale) and the Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
Patricia A
PA
Eisenach
From the Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, 06114 Halle (Saale) and.
Franziska
F
Schikora
From the Institute for Physiological Chemistry, Martin Luther University Halle-Wittenberg, 06114 Halle (Saale) and guido.posern@medizin.uni-halle.de.
Guido
G
Posern
D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D022081:Cell Surface Extensions / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D022001:Focal Adhesions; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D013634:Tannins / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D000199:Actins; D015820:Cadherins; C431575:MRTFA protein, human; D013634:Tannins; D015534:Trans-Activators; D006427:Hemin; D019881:Aminoacyltransferases; C019727:arginyltransferase
Actin; Adherens Junction; Breast Cancer; Cell Adhesion; Cell Signaling; Myocardin; Rho (Rho GTPase); Transcriptional Co-activator