scholarly journals The RhoA/Rho Kinase Pathway Regulates Nuclear Localization of Serum Response Factor

2003 ◽  
Vol 29 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Hong Wei Liu ◽  
Andrew J. Halayko ◽  
Darren J. Fernandes ◽  
Gregory S. Harmon ◽  
Joel A. McCauley ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Response Factor ◽  
Serum Response ◽  
Kinase Pathway

Nuclear import of serum response factor (SRF) requires a short amino-terminal nuclear localization sequence and is independent of the casein kinase II phosphorylation site

1994 ◽  
Vol 107 (11) ◽  
pp. 3029-3036
Author(s):  
J. Rech ◽  
I. Barlat ◽  
J.L. Veyrune ◽  
A. Vie ◽  
J.M. Blanchard
Keyword(s):  
Amino Acids ◽  
Nuclear Localization ◽  
Serum Response Factor ◽  
Phosphorylation Site ◽  
Casein Kinase Ii ◽  
Casein Kinase ◽  
Resting Cells ◽  
Response Factor ◽  
Amino Terminal ◽  
Serum Response

Serum stimulation of resting cells is mediated at least in part at the transcriptional level by the activation of numerous genes among which c-fos constitutes a model. Serum response factor (SRF) forms a ternary complex at the c-fos serum response element (SRE) with an accessory protein p62TCF/Elk-1. Both proteins are the targets of multiple phosphorylation events and their role is still unknown in the amino terminus of SRF. While the transcriptional activation domain has been mapped between amino acids 339 and 508, the DNA-binding and the dimerization domains have been mapped to between amino acids 133–235 and 168–235, respectively, no role has been proposed for the amino-terminal portion of the molecule. We demonstrate in the present work that amino acids 95 to 100 contain a stretch of basic amino acids that are sufficient to target a reporter protein to the nucleus. Moreover, this sequence appears to be the only nuclear localization signal operating in SRF. Finally, whereas the global structure around this putative nuclear location signal is reminiscent of what is found in the SV40 T antigen, the casein kinase II phosphorylation site does not determine the rate of cyto-nuclear protein transport of this protein.

scholarly journals Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling

2020 ◽  
Vol 118 (2) ◽  
pp. e2008861118
Author(s):  
Yuxuan Guo ◽  
Yangpo Cao ◽  
Blake D. Jardin ◽  
Isha Sethi ◽  
Qing Ma ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Serum Response Factor ◽  
Mitochondrial Genes ◽  
Dominant Negative ◽  
Response Factor ◽  
Strongly Correlated ◽  
Transcriptional Dysregulation ◽  
Transcriptional Changes ◽  
Major Bottleneck ◽  
Serum Response

The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.

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 LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics

2002 ◽  
Vol 157 (5) ◽  
pp. 831-838 ◽  
Author(s):  
Olivier Geneste ◽  
John W. Copeland ◽  
Richard Treisman
Keyword(s):  
Actin Polymerization ◽  
Serum Response Factor ◽  
Rho Kinase ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Response Factor ◽  
Lim Kinase ◽  
Serum Stimulation ◽  
Effector Pathways ◽  
Serum Response

The small GTPase RhoA controls activity of serum response factor (SRF) by inducing changes in actin dynamics. We show that in PC12 cells, activation of SRF after serum stimulation is RhoA dependent, requiring both actin polymerization and the Rho kinase (ROCK)–LIM kinase (LIMK)–cofilin signaling pathway, previously shown to control F-actin turnover. Activation of SRF by overexpression of wild-type LIMK or ROCK-insensitive LIMK mutants also requires functional RhoA, indicating that a second RhoA-dependent signal is involved. This is provided by the RhoA effector mDia: dominant interfering mDia1 derivatives inhibit both serum- and LIMK-induced SRF activation and reduce the ability of LIMK to induce F-actin accumulation. These results demonstrate a role for LIMK in SRF activation, and functional cooperation between RhoA-controlled LIMK and mDia effector pathways.

scholarly journals Senescence represses the nuclear localization of the serum response factor and differentiation regulates its nuclear localization with lineage specificity

2001 ◽  
Vol 114 (5) ◽  
pp. 1011-1018
Author(s):  
W. Ding ◽  
S. Gao ◽  
R.E. Scott
Keyword(s):  
Growth Factor ◽  
Nuclear Localization ◽  
Adipocyte Differentiation ◽  
Serum Response Factor ◽  
Growth Control ◽  
Proliferative Potential ◽  
Response Factor ◽  
Opposite Manner ◽  
Serum Response

The differentiation of cultured 3T3T mesenchymal stem cells into adipocytes represses growth factor responsiveness by limiting the nuclear localization of the serum response factor (SRF) that binds to and activates the promoters of growth control genes that contain the serum response elements (SRE), such as junB and c-fos. The regulation of SRF nuclear localization by adipocyte differentiation is specific, because we show that adipocyte differentiation does not repress the nuclear localization of six other transacting factors. To determine if repression of growth factor responsiveness that occurs during senescence also represses the nuclear localization of SRF, we studied normal human WI-38 fibroblasts at low versus high population doublings. The results show that SRF localizes to the nucleus of proliferative cells whereas in senescent cells SRF can not be detected in the nucleus. This result is apparent in both immunofluorescence assays and in western blot analysis. We next evaluated the cellular distribution of SRF in selected human tissues to determine whether the loss of proliferative potential in vivo could have a different effect on SRF nuclear localization. We found that in cells of the small bowel mucosa, differentiation modulates SRF nuclear localization in an opposite manner. Minimal SRF expression and nuclear localization is evident in undifferentiated cells at the base of crypts whereas increased SRF expression and nuclear localization is evident in differentiated cells at the surface tip of the villus. These results together establish that regulation of SRF expression and nuclear localization is important in senescence and differentiation in a lineage specific manner.

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.

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