Actin Dynamics Control SRF Activity by Regulation of Its Coactivator MAL

Abstract

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.

Phosphorylation of the cytokinesis regulator ECT2 at G2/M phase stimulates association of the mitotic kinase Plk1 and accumulation of GTP-bound RhoA

“…In contrast, the phosphomimic mutant T412D did induce the accumulation of RhoA. Moreover, WT ECT2 and the T412D mutant stimulated SRFregulated transcriptional activity, which is controlled by actin polymerization through Rho GTPases (Hill et al, 1995;Miralles et al, 2003), whereas the activity of the T412A mutant was significantly reduced. While the T to A substitution is believed to be structurally conservative, one might think that the loss of function of ECT2 T412A was due to the generation of a nonfunctional form as a result of a drastic structural change rather than an inability to be phosphorylated.…”

Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

“…The means whereby mechanical stress induces myofibroblast differentiation are still unknown. One possibility is the engagement of MRTF-A which translocates to the nucleus in response to mechanical stress in a Rho kinase-dependent manner [39,40] and has also been shown to cause myofibroblast marker gene expression in cardiac fibroblasts [41]. Interestingly, RhoA activity (which in turn activates Rho kinase) is reduced in cardiac fibroblasts from syndecan-4 -/-mice [33].…”

Hepatocyte Growth Factor-induced Ras Activation Requires ERM Proteins Linked to Both CD44v6 and F-Actin

“…Here, free G-actin inhibits SRF activity by sequestering a coactivator, MAL, in the cytoplasm (Miralles et al, 2003). The SRF/MAL complex addresses a subset of SRF target genes (Treisman et al, 1998).…”