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, 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.
Miralles
Francesc
F
Transcription Laboratory, Room 401, Cancer Research UK London Research Institute, Lincolns Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Posern
Guido
G
Zaromytidou
Alexia-Ileana
AI
Treisman
Richard
R
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; D046911:Macromolecular Substances; D015514:Oncogene Proteins, Fusion; D026362:Serum Response Factor; D015534:Trans-Activators; D004247:DNA; D020741:rho GTP-Binding Proteins