Inhibition of arginyltransferase 1 induces MRTF-A’s transcriptional activity and promotes directional migration [Signal Transduction]

November 7th, 2014 by Eisenach, P. A., Schikora, F., Posern, G.

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. Whilst arginylated actin did not differentially affect MRTF-A, a rapid loss of E-cadherin and F-actin reorganization preceeded 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 MRTF.