MAL/MRTF-A controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins.
Monomeric actin regulates gene expression through serum response factor (SRF) by inhibiting its transcriptional coactivator myocardin-related transcription factor (MAL/MRTF). Many affected genes encode cytoskeletal components. We have analysed the migratory effects of actin-MAL signalling and of new target genes in non-invasive highly adherent cells. Expression of active MAL impaired migration of both fibroblasts and epithelial cells, whereas dominant-negative constructs and partial knockdown of MAL/MRTF enhanced motility. Knockdown of three newly characterised G-actin-regulated MAL targets, integrin α5, plakophilin 2 (Pkp2) and FHL1, enhanced cell migration. All three were upregulated by external stimulation through actin-MAL-SRF signalling, and MAL and SRF were inducibly recruited to cis-regulatory elements of the integrin α5 and Pkp2 genes. Finally, the reduced migration of epithelial cells stably expressing MAL was partially reversed by knockdown of Pkp2 and FHL1. We conclude that the actin-MAL pathway promotes adhesive gene expression, including integrin α5, Pkp2 and FHL1, and that this is anti-motile for non-invasive cells harbouring high basal activity.
AG Regulation of Gene Expression, Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried,  Germany.
Laura
L
Leitner
Dmitry
D
Shaposhnikov
Alexander
A
Mengel
Arnaud
A
Descot
Sylvia
S
Julien
Reinhard
R
Hoffmann
Guido
G
Posern
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004847:Epithelial Cells / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D039564:Integrin alphaV / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D041681:NIH 3T3 Cells; D051191:Plakophilins / Q000037:antagonists & inhibitors / Q000235:genetics; D011401:Promoter Regions, Genetic; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D015854:Up-Regulation
D000199:Actins; D003598:Cytoskeletal Proteins; C486306:Fhl1 protein, mouse; D039564:Integrin alphaV; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C511173:Mrtfa protein, mouse; D009124:Muscle Proteins; D051191:Plakophilins; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C503315:myocardin-related transcription factor B, mouse