ausblenden:
Schlagwörter:
SRF-MEDIATED TRANSCRIPTION, SERUM RESPONSE FACTOR, END RULE PATHWAY,
MEGAKARYOBLASTIC LEUKEMIA, ACTIN DYNAMICS, CELL MOTILITY, ARGINYLATION,
PROTEIN, MKL1, PHOSPHORYLATIONBiochemistry & Molecular Biology; Biophysics; Actin, Adherens Junction, Breast Cancer, Cell Adhesion, Cell Signaling,
Myocardin, Rho (Rho GTPase), Transcriptional Co-activator;
Zusammenfassung:
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.
