scholarly journals The actin-MRTF-SRF transcriptional circuit controls tubulin acetylation via α-TAT1 gene expression

2018 ◽  
Vol 217 (3) ◽  
pp. 929-944 ◽  
Author(s):  
Jaime Fernández-Barrera ◽  
Miguel Bernabé-Rubio ◽  
Javier Casares-Arias ◽  
Laura Rangel ◽  
Laura Fernández-Martín ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Cell Types ◽  
Mrna Levels ◽  
Tubulin Acetylation ◽  
Hereditary Disorders ◽  
Related Transcription Factor ◽  
Transcriptional Complex ◽  
Serum Response

The role of formins in microtubules is not well understood. In this study, we have investigated the mechanism by which INF2, a formin mutated in degenerative renal and neurological hereditary disorders, controls microtubule acetylation. We found that silencing of INF2 in epithelial RPE-1 cells produced a dramatic drop in tubulin acetylation, increased the G-actin/F-actin ratio, and impaired myocardin-related transcription factor (MRTF)/serum response factor (SRF)–dependent transcription, which is known to be repressed by increased levels of G-actin. The effect on tubulin acetylation was caused by the almost complete absence of α-tubulin acetyltransferase 1 (α-TAT1) messenger RNA (mRNA). Activation of the MRTF-SRF transcriptional complex restored α-TAT1 mRNA levels and tubulin acetylation. Several functional MRTF-SRF–responsive elements were consistently identified in the α-TAT1 gene. The effect of INF2 silencing on microtubule acetylation was also observed in epithelial ECV304 cells, but not in Jurkat T cells. Therefore, the actin-MRTF-SRF circuit controls α-TAT1 transcription. INF2 regulates the circuit, and hence microtubule acetylation, in cell types where it has a prominent role in actin polymerization.

scholarly journals Enhancement of mDia2 activity by Rho-kinase-dependent phosphorylation of the diaphanous autoregulatory domain

2011 ◽  
Vol 439 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Dean P. Staus ◽  
Joan M. Taylor ◽  
Christopher P. Mack
Keyword(s):  
Smooth Muscle ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Specific Gene ◽  
Related Transcription Factor ◽  
Inhibitory Domain ◽  
Serum Response ◽  
Acidic Region ◽  
Basic Region

It is clear that RhoA activates the DRF (diaphanous-related formin) mDia2 by disrupting the molecular interaction between the DAD (diaphanous autoregulatory domain) and the DID (diaphanous inhibitory domain). Previous studies indicate that a basic motif within the DAD contributes to mDia2 auto-inhibition, and results shown in the present study suggest these residues bind a conserved acidic region within the DID. Furthermore, we demonstrate that mDia2 is phosphorylated by ROCK (Rho-kinase) at two conserved residues (Thr1061 and Ser1070) just C-terminal to the DAD basic region. Phosphomimetic mutations to these residues in the context of the full-length molecule enhanced mDia2 activity as measured by increased actin polymerization, SRF (serum response factor)-dependent smooth muscle-specific gene transcription, and nuclear localization of myocardin-related transcription factor B. Biochemical and functional data indicate that the T1061E/S1070E mutation significantly inhibited the ability of DAD to interact with DID and enhanced mDia2 activation by RhoA. Taken together, the results of the present study indicate that ROCK-dependent phosphorylation of the mDia2 DAD is an important determinant of mDia2 activity and that this signalling mechanism affects actin polymerization and smooth muscle cell-specific gene expression.

scholarly journals The nature and intensity of mechanical stimulation drive different dynamics of MRTF-A nuclear redistribution after actin remodeling in myoblasts

2018 ◽  
Author(s):  
Lorraine Montel ◽  
Athanassia Sotiropoulos ◽  
Sylvie Hénon
Keyword(s):  
Mechanical Stimulation ◽  
Actin Polymerization ◽  
Target Genes ◽  
Serum Response Factor ◽  
Magnetic Tweezers ◽  
Point Of View ◽  
Nuclear Accumulation ◽  
Related Transcription Factor ◽  
Global Increase ◽  
Serum Response

AbstractSerum response factor and its cofactor myocardin-related transcription factor (MRTF) are key elements of muscle-mass adaptation to workload. The transcription of target genes is activated when MRTF is present in the nucleus. The localization of MRTF is controlled by its binding to G-actin. Thus, the pathway can be mechanically activated through the mechanosensitivity of the actin cytoskeleton. The pathway has been widely investigated from a biochemical point of view, but its mechanical activation and the timescales involved are poorly understood. Here, we applied local and global mechanical cues to myoblasts through two custom-built set-ups, magnetic tweezers and stretchable substrates. Both induced nuclear accumulation of MRTF-A. However, the dynamics of the response varied with the nature and level of mechanical stimulation and correlated with the polymerization of different actin sub-structures. Local repeated force induced local actin polymerization and nuclear accumulation of MRTF-A by 30 minutes, whereas a global static strain induced both rapid (minutes) transient nuclear accumulation, associated with the polymerization of an actin cap above the nucleus, and long-term (hours) accumulation, with a global increase in polymerized actin. Conversely, high strain induced actin depolymerization at intermediate times, associated with cytoplasmic MRTF accumulation.

scholarly journals Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding

2016 ◽  
Vol 36 (10) ◽  
pp. 1526-1539 ◽  
Author(s):  
Julia Weissbach ◽  
Franziska Schikora ◽  
Anja Weber ◽  
Michael Kessels ◽  
Guido Posern
Keyword(s):  
Serum Response Factor ◽  
De Novo ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Serum Stimulation ◽  
Competitive Mechanism ◽  
Related Transcription Factor ◽  
Simultaneous Inhibition ◽  
Serum Response

The myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF)-mediated gene expression. Activation of MRTF-A occurs in response to alterations in actin dynamics and critically requires the dissociation of repressive G-actin–MRTF-A complexes. However, the mechanism leading to the release of MRTF-A remains unclear. Here we show that WH2 domains compete directly with MRTF-A for actin binding. Actin nucleation-promoting factors, such as N-WASP and WAVE2, as well as isolated WH2 domains, including those of Spire2 and Cobl, activate MRTF-A independently of changes in actin dynamics. Simultaneous inhibition of Arp2-Arp3 or mutation of the CA region only partially reduces MRTF-A activation by N-WASP and WAVE2. Recombinant WH2 domains and the RPEL domain of MRTF-A bind mutually exclusively to cellular and purified G-actinin vitro. The competition by different WH2 domains correlates with MRTF-SRF activation. Following serum stimulation, nonpolymerizable actin dissociates from MRTF-A, andde novoformation of the G-actin–RPEL complex is impaired by a transferable factor. Our work demonstrates that WH2 domains activate MRTF-A and contribute to target gene regulation by a competitive mechanism, independently of their role in actin filament formation.

scholarly journals Serum response factor binding sites differ in three human cell types

2007 ◽  
Vol 17 (2) ◽  
pp. 136-144 ◽  
Author(s):  
S. J. Cooper ◽  
N. D. Trinklein ◽  
L. Nguyen ◽  
R. M. Myers
Keyword(s):  
Human Cell ◽  
Binding Sites ◽  
Serum Response Factor ◽  
Cell Types ◽  
Response Factor ◽  
Factor Binding ◽  
Serum Response

scholarly journals Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sergi Marco ◽  
Matthew Neilson ◽  
Madeleine Moore ◽  
Arantxa Perez-Garcia ◽  
Holly Hall ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Tyrosine Kinases ◽  
Target Genes ◽  
Serum Response Factor ◽  
Actin Binding ◽  
Cell Scattering ◽  
Nuclear Localisation Sequence ◽  
Related Transcription Factor ◽  
Endosomal System ◽  
Serum Response

AbstractSignals are relayed from receptor tyrosine kinases (RTKs) at the cell surface to effector systems in the cytoplasm and nucleus, and coordination of this process is important for the execution of migratory phenotypes, such as cell scattering and invasion. The endosomal system influences how RTK signalling is coded, but the ways in which it transmits these signals to the nucleus to influence gene expression are not yet clear. Here we show that hepatocyte growth factor, an activator of MET (an RTK), promotes Rab17- and clathrin-dependent endocytosis of EphA2, another RTK, followed by centripetal transport of EphA2-positive endosomes. EphA2 then mediates physical capture of endosomes on the outer surface of the nucleus; a process involving interaction between the nuclear import machinery and a nuclear localisation sequence in EphA2’s cytodomain. Nuclear capture of EphA2 promotes RhoG-dependent phosphorylation of the actin-binding protein, cofilin to oppose nuclear import of G-actin. The resulting depletion of nuclear G-actin drives transcription of Myocardin-related transcription factor (MRTF)/serum-response factor (SRF)-target genes to implement cell scattering and the invasive behaviour of cancer cells.

scholarly journals The Diaphanous-related Formin mDia1 Controls Serum Response Factor Activity through its Effects on Actin Polymerization

2002 ◽  
Vol 13 (11) ◽  
pp. 4088-4099 ◽  
Author(s):  
John W. Copeland ◽  
Richard Treisman
Keyword(s):  
Actin Polymerization ◽  
Serum Response Factor ◽  
Signal Pathway ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Actin Assembly ◽  
Extracellular Signals ◽  
Activation Assay ◽  
The Relationship ◽  
Serum Response

SRF-dependent transcription is regulated by the small GTPase RhoA via its effects on actin dynamics. The diaphanous-related formin (DRF) proteins have been identified as candidate RhoA effectors mediating signaling to SRF. Here we investigate the relationship between SRF activation and actin polymerization by the DRF mDia1. We show that the ability of mDia1 to potentiate SRF activity is strictly correlated with its ability to promote F-actin assembly. Both processes can occur independently of the mDia1 FH1 domain but require sequences in an extended C-terminal region encompassing the conserved FH2 domain. mDia-mediated SRF activation, but not F-actin assembly, can be blocked by a nonpolymerizable actin mutant, placing actin downstream of mDia in the signal pathway. The SRF activation assay was used to identify inactive mDia1 derivatives that inhibit serum- and LPA-induced signaling to SRF. We show that these interfering mutants also block F-actin assembly, whether induced by mDia proteins or extracellular signals. These results identify novel functional elements of mDia1 and show that it regulates SRF activity by inducing depletion of the cellular pool of G-actin.

scholarly journals MRTF: Basic Biology and Role in Kidney Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 6040
Author(s):  
Maria Zena Miranda ◽  
Zsuzsanna Lichner ◽  
Katalin Szászi ◽  
András Kapus
Keyword(s):  
Kidney Disease ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Inflammatory Responses ◽  
Regulation Of Gene Expression ◽  
Rho Family Gtpases ◽  
Epithelial Phenotype ◽  
Related Transcription Factor ◽  
Cytoskeleton Remodeling ◽  
Basic Biology

A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.

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