Actin Dynamics Control SRF Activity by Regulation of Its Coactivator MAL

Rho GTPases regulate the transcription factor SRF via their ability to induce actin polymerization. SRF activity responds to G actin, but the mechanism of this has remained unclear. We show that Rho-actin signaling regulates the subcellular localization of the myocardin-related SRF coactivator MAL,...

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Bibliographic Details
Published in:Cell 2003-05, Vol.113 (3), p.329-342
Main Authors: Miralles, Francesc, Posern, Guido, Zaromytidou, Alexia-Ileana, Treisman, Richard
Format: Article
Language:English
Subjects:
3T3 Cells
Actins - metabolism
Active Transport, Cell Nucleus
Amino Acid Motifs
Amino Acid Sequence
Animals
Binding Sites
Cell Line
Cell Nucleus - metabolism
Conserved Sequence
DNA - metabolism
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Electrophoretic Mobility Shift Assay
Humans
Macromolecular Substances
Mice
Molecular Sequence Data
Oncogene Proteins, Fusion - chemistry
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Phosphorylation
rho GTP-Binding Proteins - metabolism
Serum Response Factor - metabolism
Signal Transduction
Trans-Activators
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Summary:Rho GTPases regulate the transcription factor SRF via their ability to induce actin polymerization. SRF activity responds to G actin, but the mechanism of this has remained unclear. We show that Rho-actin signaling regulates the subcellular localization of the myocardin-related SRF coactivator MAL, rearranged in t(1;22)(p13;q13) AML. The MAL-SRF interaction displays the predicted properties of a Rho-regulated SRF cofactor. MAL is predominantly cytoplasmic in serum-starved cells, but accumulates in the nucleus following serum stimulation. Activation of the Rho-actin signaling pathway is necessary and sufficient to promote MAL nuclear accumulation. MAL N-terminal sequences, including two RPEL motifs, are required for the response to signaling, while other regions mediate its nuclear export (or cytoplasmic retention) and nuclear import. MAL associates with unpolymerized actin through its RPEL motifs. Constitutively cytoplasmic MAL derivatives interfere with MAL redistribution and Rho-actin signaling to SRF. MAL associates with several SRF target promoters regulated via the Rho-actin pathway.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(03)00278-2