Abstract
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.
Highlights
The transcriptional co-activator MRTF-A is regulated by changes in actin dynamics
We report that inhibition of arginyltransferase 1 (ATE1), an enzyme mediating posttranscriptional protein arginylation, is sufficient to increase MRTF-A activity in MCF-7 human breast carcinoma cells independently of external growth factor stimuli
We report that inhibition of arginyltransferase 1 (ATE1), an enzyme mediating protein arginylation, is sufficient to activate MRTF-A activity in resting MCF-7 cells in a manner that appears to be independent of direct N-terminal arginylation of -actin
Summary
The transcriptional co-activator MRTF-A is regulated by changes in actin dynamics. Results: Inhibition of ATE1 activates MRTF-A and modulates directed migration of breast cancer cells. 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. We report that inhibition of arginyltransferase 1 (ATE1), an enzyme mediating posttranscriptional protein arginylation, is sufficient to increase MRTF-A activity in MCF-7 human breast carcinoma cells independently of external growth factor stimuli. Monomeric actin (G-actin) is known to sequester MRTF-A’s transcriptional activity of controlling SRF-dependent target gene expression by binding to its N-terminal RPEL motifs [3]. This inhibitory complex formation may be reversed in growth factor-stimulated cells, leading to nuclear accumulation and transcriptional activation of MRTF-A.
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