PT  - JOURNAL ARTICLE
AU  - Kircher, Philipp
AU  - Hermanns, Constanze
AU  - Nossek, Maximilian
AU  - Drexler, Maria Katharina
AU  - Grosse, Robert
AU  - Fischer, Maximilian
AU  - Sarikas, Antonio
AU  - Penkava, Josef
AU  - Lewis, Thera
AU  - Prywes, Ron
AU  - Gudermann, Thomas
AU  - Muehlich, Susanne
TI  - Filamin A interacts with the coactivator MKL1 to promote the activity of the transcription factor SRF and cell migration
AID  - 10.1126/scisignal.aad2959
DP  - 2015 Nov 10
TA  - Science Signaling
PG  - ra112--ra112
VI  - 8
IP  - 402
4099  - http://stke.sciencemag.org/content/8/402/ra112.short
4100  - http://stke.sciencemag.org/content/8/402/ra112.full
SO  - Sci. Signal.2015 Nov 10; 8
AB  - The highly dynamic actin cytoskeleton maintains cell shape, enables cell movement, and contributes to cell division. Perhaps surprisingly, actin cytoskeletal dynamics also regulate gene expression. Persistent cell migration involves both cytoskeletal reorganization and expression of specific genes. The transcription factor serum response factor (SRF) and the coactivator megakaryoblastic leukemia 1 (MKL1) mediate transcriptional changes in response to external signals that affect actin dynamics. Globular actin (G-actin) keeps MKL1 in the cytosol, and signals that promote the formation of filamentous actin (F-actin) trigger the nuclear translocation of MKL1 and transcriptional activation of SRF. MKL1 not only had to dissociate from G-actin but also had to associate with the F-actin binding protein filamin A (FLNA) to promote SRF activity. Indeed, FLNA bound to the promoters of the same genes that are regulated by MKL1-SRF. Blocking the interaction between FLNA and MKL1—by inhibiting actin polymerization, mutating the FLNA interaction site on MKL1, or reducing the amount of FLNA—impaired the expression of MKL1-SRF target genes. Thus, actin dynamics not only actively move cells but also actively mediate the transcriptional activity of regulators needed for cellular movement.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.