scholarly journals Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL

2008 ◽  
Vol 27 (23) ◽  
pp. 3198-3208 ◽  
Author(s):  
Stephane Mouilleron ◽  
Sebastian Guettler ◽  
Carola A Langer ◽  
Richard Treisman ◽  
Neil Q McDonald
Keyword(s):  
Molecular Basis ◽  
Serum Response Factor ◽  
Actin Binding ◽  
Response Factor ◽  
Serum Response

scholarly journals Serum-Induced Phosphorylation of the Serum Response Factor Coactivator MKL1 by the Extracellular Signal-Regulated Kinase 1/2 Pathway Inhibits Its Nuclear Localization

2008 ◽  
Vol 28 (20) ◽  
pp. 6302-6313 ◽  
Author(s):  
Susanne Muehlich ◽  
Ruigong Wang ◽  
Seung-Min Lee ◽  
Thera C. Lewis ◽  
Chao Dai ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Nuclear Export ◽  
Serum Response Factor ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Actin Binding ◽  
Response Factor ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Serum Response

ABSTRACT Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related coactivator of the serum response factor (SRF) transcription factor, which has an integral role in differentiation, migration, and proliferation. Serum induces RhoA-dependent translocation of MKL1 from the cytoplasm to the nucleus and also causes a rapid increase in MKL1 phosphorylation. We have mapped a serum-inducible phosphorylation site and found, surprisingly, that its mutation causes constitutive localization to the nucleus, suggesting that phosphorylation of MKL1 inhibits its serum-induced nuclear localization. The key site, serine 454, resembles a mitogen-activated protein kinase phosphorylation site, and its modification was blocked by the MEK1 inhibitor U0126, implying that extracellular signal-regulated kinase 1/2 (ERK1/2) is the serum-inducible kinase that phosphorylates MKL1. Previous results indicated that G-actin binding to MKL1 promotes its nuclear export, and we found that MKL1 phosphorylation is required for its binding to actin, explaining its effect on localization. We propose a model in which serum induction initially stimulates MKL1 nuclear localization due to a decrease in G-actin levels, but MKL1 is then downregulated by nuclear export due to ERK1/2 phosphorylation.

scholarly journals A novel function of the monomeric CCTε subunit connects the serum response factor pathway to chaperone-mediated actin folding

2015 ◽  
Vol 26 (15) ◽  
pp. 2801-2809 ◽  
Author(s):  
Kerryn L. Elliott ◽  
Andreas Svanström ◽  
Matthias Spiess ◽  
Roger Karlsson ◽  
Julie Grantham
Keyword(s):  
Mammalian Cells ◽  
Actin Polymerization ◽  
Serum Response Factor ◽  
Actin Binding ◽  
Nuclear Accumulation ◽  
Response Factor ◽  
Actin Assembly ◽  
Actin Expression ◽  
Serum Response ◽  
Substrate Binding Domain

Correct protein folding is fundamental for maintaining protein homeostasis and avoiding the formation of potentially cytotoxic protein aggregates. Although some proteins appear to fold unaided, actin requires assistance from the oligomeric molecular chaperone CCT. Here we report an additional connection between CCT and actin by identifying one of the CCT subunits, CCTε, as a component of the myocardin-related cotranscription factor-A (MRTF-A)/serum response factor (SRF) pathway. The SRF pathway registers changes in G-actin levels, leading to the transcriptional up-regulation of a large number of genes after actin polymerization. These genes encode numerous actin-binding proteins as well as actin. We show that depletion of the CCTε subunit by siRNA enhances SRF signaling in cultured mammalian cells by an actin assembly-independent mechanism. Overexpression of CCTε in its monomeric form revealed that CCTε binds via its substrate-binding domain to the C-terminal region of MRTF-A and that CCTε is able to alter the nuclear accumulation of MRTF-A after stimulation by serum addition. Given that the levels of monomeric CCTε conversely reflect the levels of CCT oligomer, our results suggest that CCTε provides a connection between the actin-folding capacity of the cell and actin expression.

scholarly journals RPEL Motifs Link the Serum Response Factor Cofactor MAL but Not Myocardin to Rho Signaling via Actin Binding

2007 ◽  
Vol 28 (2) ◽  
pp. 732-742 ◽  
Author(s):  
Sebastian Guettler ◽  
Maria K. Vartiainen ◽  
Francesc Miralles ◽  
Banafshe Larijani ◽  
Richard Treisman
Keyword(s):  
Transcription Factor ◽  
Family Member ◽  
Serum Response Factor ◽  
Rho Gtpase ◽  
Nucleocytoplasmic Transport ◽  
Actin Binding ◽  
Response Factor ◽  
Nucleocytoplasmic Shuttling ◽  
Related Transcription Factor ◽  
Serum Response

ABSTRACT Myocardin (MC) family proteins are transcriptional coactivators for serum response factor (SRF). Each family member possesses a conserved N-terminal region containing three RPEL motifs (the “RPEL domain”). MAL/MKL1/myocardin-related transcription factor A is cytoplasmic, accumulating in the nucleus upon activation of Rho GTPase signaling, which alters interactions between G-actin and the RPEL domain. We demonstrate that MC, which is nuclear, does not shuttle through the cytoplasm and that the contrasting nucleocytoplasmic shuttling properties of MAL and MC are defined by their RPEL domains. We show that the MAL RPEL domain binds actin more avidly than that of MC and that the RPEL motif itself is an actin-binding element. RPEL1 and RPEL2 of MC bind actin weakly compared with those of MAL, while RPEL3 is of comparable and low affinity in the two proteins. Actin binding by all three motifs is required for MAL regulation. The differing behaviors of MAL and MC are specified by the RPEL1-RPEL2 unit, while RPEL3 can be exchanged between them. We propose that differential actin occupancy of multiple RPEL motifs regulates nucleocytoplasmic transport and activity of MAL.

scholarly journals Muscle-Specific Signaling Mechanism That Links Actin Dynamics to Serum Response Factor

2005 ◽  
Vol 25 (8) ◽  
pp. 3173-3181 ◽  
Author(s):  
Koichiro Kuwahara ◽  
Tomasa Barrientos ◽  
G. C. Teg Pipes ◽  
Shijie Li ◽  
Eric N. Olson
Keyword(s):  
Actin Polymerization ◽  
Serum Response Factor ◽  
Striated Muscle ◽  
Nuclear Translocation ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Response Factor ◽  
Signaling Mechanism ◽  
Muscle Gene Expression ◽  
Serum Response

ABSTRACT Myocardin and the myocardin-related transcription factors (MRTFs) MRTF-A and MRTF-B are coactivators for serum response factor (SRF), which regulates genes involved in cell proliferation, migration, cytoskeletal dynamics, and myogenesis. MRTF-A has been shown to translocate to the nucleus and activate SRF in response to Rho signaling and actin polymerization. Previously, we described a muscle-specific actin-binding protein named striated muscle activator of Rho signaling (STARS) that also activates SRF through a Rho-dependent mechanism. Here we show that STARS activates SRF by inducing the nuclear translocation of MRTFs. The STARS-dependent nuclear import of MRTFs requires RhoA and actin polymerization, and the actin-binding domain of STARS is necessary and sufficient for this activity. A knockdown of endogenous STARS expression by using small interfering RNA significantly reduced SRF activity in differentiated C2C12 skeletal muscle cells and cardiac myocytes. The ability of STARS to promote the nuclear localization of MRTFs and SRF-mediated transcription provides a potential muscle-specific mechanism for linking changes in actin dynamics and sarcomere structure with striated muscle gene expression.

scholarly journals The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor

2021 ◽  
Vol 8 (5) ◽  
pp. 58
Author(s):  
Hazel Aberdeen ◽  
Kaela Battles ◽  
Ariana Taylor ◽  
Jeranae Garner-Donald ◽  
Ana Davis-Wilson ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Response Factor ◽  
Homeostatic Control ◽  
Older Americans ◽  
The Subject ◽  
Serum Response

The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hypoglycemia remain unclear and the subject of much debate. In this review, the molecular basis of the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular lesions and injury are discussed. Further, we review the potential role of the serum response factor (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins.

A novel ortholog of serum response factor (SRF) with immune defense function identified in Crassostrea hongkongensis

2014 ◽  
Vol 36 (1) ◽  
pp. 75-82 ◽  
Author(s):  
Zhiming Xiang ◽  
Fufa Qu ◽  
Lin Qi ◽  
Yang Zhang ◽  
Shu Xiao ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Immune Defense ◽  
Response Factor ◽  
Crassostrea Hongkongensis ◽  
Serum Response ◽  
Defense Function
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