Complexities in ETS-Domain Transcription Factor Function and Regulation: Lessons from the TCF (Ternary Complex Factor) Subfamily

2002 ◽  
Vol 30 (2) ◽  
pp. 1-9 ◽  
Author(s):  
A. D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Ternary Complex ◽  
Serum Response Factor ◽  
Mitogen Activated Protein Kinase ◽  
Functional Conservation ◽  
Transcriptional Regulatory ◽  
Mitogen Activated Protein ◽  
Ets Domain ◽  
Ternary Complex Factor

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

scholarly journals Determinants of DNA-binding specificity of ETS-domain transcription factors.

1996 ◽  
Vol 16 (7) ◽  
pp. 3338-3349 ◽  
Author(s):  
P Shore ◽  
A J Whitmarsh ◽  
R Bhaskaran ◽  
R J Davis ◽  
J P Waltho ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Serum Response Factor ◽  
Binding Specificity ◽  
Mitogen Activated Protein Kinase ◽  
Critical Determinant ◽  
Binding Interface ◽  
Dna Binding Specificity ◽  
Mitogen Activated Protein ◽  
Ets Domain

Several mechanisms are employed by members of transcription factor families to achieve sequence-specific DNA recognition. In this study, we have investigated how members of the ETS-domain transcription factor family achieve such specificity. We have used the ternary complex factor (TCF) subfamily as an example. ERK2 mitogen-activated protein kinase stimulates serum response factor-dependent and autonomous DNA binding by the TCFs Elk-1 and SAP-la. Phosphorylated Elk-1 and SAP-la exhibit specificities of DNA binding similar to those of their isolated ETS domains. The ETS domains of Elk-1 and SAP-la and SAP-2 exhibit related but distinct DNA-binding specificities. A single residue, D-69 (Elk-1) or V-68 (SAP-1), has been identified as the critical determinant for the differential binding specificities of Elk-1 and SAP-1a, and an additional residue, D-38 (Elk-1) or Q-37 (SAP-1), further modulates their DNA binding. Creation of mutations D38Q and D69V is sufficient to confer SAP-la DNA-binding specificity upon Elk-1 and thereby allow it to bind to a greater spectrum of sites. Molecular modelling indicates that these two residues (D-38 and D-69) are located away from the DNA-binding interface of Elk-1. Our data suggest a mechanism in which these residues modulate DNA binding by influencing the interaction of other residues with DNA.

scholarly journals ABIN-2 Forms a Ternary Complex with TPL-2 and NF-κB1 p105 and Is Essential for TPL-2 Protein Stability

2004 ◽  
Vol 24 (12) ◽  
pp. 5235-5248 ◽  
Author(s):  
V. Lang ◽  
A. Symons ◽  
S. J. Watton ◽  
J. Janzen ◽  
Y. Soneji ◽  
...  
Keyword(s):  
Ternary Complex ◽  
Affinity Purification ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Steady State Levels ◽  
Mek Kinase ◽  
Tlr4 Activation ◽  
Lps Activation

ABSTRACT NF-κB1 p105 forms a high-affinity, stoichiometric interaction with TPL-2, a MEK kinase essential for TLR4 activation of the ERK mitogen-activated protein kinase cascade in lipopolysaccharide (LPS)-stimulated macrophages. Interaction with p105 is required to maintain TPL-2 metabolic stability and also negatively regulates TPL-2 MEK kinase activity. Here, affinity purification identified A20-binding inhibitor of NF-κB 2 (ABIN-2) as a novel p105-associated protein. Cotransfection experiments demonstrated that ABIN-2 could interact with TPL-2 in addition to p105 but preferentially formed a ternary complex with both proteins. Consistently, in unstimulated bone marrow-derived macrophages (BMDMs), a substantial fraction of endogenous ABIN-2 was associated with both p105 and TPL-2. Although the majority of TPL-2 in these cells was complexed with ABIN-2, the pool of TPL-2 which could activate MEK after LPS stimulation was not, and LPS activation of TPL-2 was found to correlate with its release from ABIN-2. Depletion of ABIN-2 by RNA interference dramatically reduced steady-state levels of TPL-2 protein without affecting levels of TPL-2 mRNA or p105 protein. In addition, ABIN-2 increased the half-life of cotransfected TPL-2. Thus, optimal TPL-2 stability in vivo requires interaction with ABIN-2 as well as p105. Together, these data raise the possibility that ABIN-2 functions in the TLR4 signaling pathway which regulates TPL-2 activation.

scholarly journals Role for the Ran Binding Protein, Mog1p, in Saccharomyces cerevisiae SLN1-SKN7 Signal Transduction

2004 ◽  
Vol 3 (6) ◽  
pp. 1544-1556 ◽  
Author(s):  
Jade Mei-Yeh Lu ◽  
Robert J. Deschenes ◽  
Jan S. Fassler
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Osmotic Response ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

ABSTRACT Yeast Sln1p is an osmotic stress sensor with histidine kinase activity. Modulation of Sln1 kinase activity in response to changes in the osmotic environment regulates the activity of the osmotic response mitogen-activated protein kinase pathway and the activity of the Skn7p transcription factor, both important for adaptation to changing osmotic stress conditions. Many aspects of Sln1 function, such as how kinase activity is regulated to allow a rapid response to the continually changing osmotic environment, are not understood. To gain insight into Sln1p function, we conducted a two-hybrid screen to identify interactors. Mog1p, a protein that interacts with the yeast Ran1 homolog, Gsp1p, was identified in this screen. The interaction with Mog1p was characterized in vitro, and its importance was assessed in vivo. mog1 mutants exhibit defects in SLN1-SKN7 signal transduction and mislocalization of the Skn7p transcription factor. The requirement for Mog1p in normal localization of Skn7p to the nucleus does not fully account for the mog1-related defects in SLN1-SKN7 signal transduction, raising the possibility that Mog1p may play a role in Skn7 binding and activation of osmotic response genes.

VEGFD regulates blood vascular development by modulating SOX18 activity

Blood ◽  
2014 ◽  
Vol 123 (7) ◽  
pp. 1102-1112 ◽  
Author(s):  
Tam Duong ◽  
Katarzyna Koltowska ◽  
Cathy Pichol-Thievend ◽  
Ludovic Le Guen ◽  
Frank Fontaine ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Vascular Development ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Key Points ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

Key Points Haploinsufficiency of Sox18 reveals an important role for VEGFD in regulating blood vascular development in vivo in vertebrates. VEGFD acts through mitogen-activated protein kinase kinase–extracellular signal-regulated kinase to modulate the activity and nuclear concentration of endothelial-specific transcription factor SOX18.

Convergence of the SUMO and MAPK pathways on the ETS-domain transcription factor Elk-1

2006 ◽  
Vol 73 ◽  
pp. 121-129 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Highly Active ◽  
Molecular Events ◽  
Extracellular Signal ◽  
Activated State ◽  
Mitogen Activated Protein ◽  
Ets Domain

The ETS-domain transcription factor Elk-1 is regulated by phosphorylation in response to activation of the MAPK (mitogen-activated protein kinase) pathways. This phosphorylation triggers a series of molecular events that convert Elk-1 from a transcriptionally silent state into a highly active state and then back to a basal level. At the same time, activation of the ERK (extracellular-signal-regulated kinase) MAPK pathway leads to loss of modification of Elk-1 by SUMO (small ubiquitin-related modifier). As SUMO imparts repressive properties on Elk-1, ERK-mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1. Thus a two-step mechanism is employed to convert Elk-1 into its fully activated state. Here, the molecular events underlying these changes in Elk-1 status, and the role of PIASxα [protein inhibitor of activated STAT (signal transducer and activator of transcription) xα] as a co-activator that facilitates this process, are discussed.

scholarly journals The Ternary Complex Factor Net Regulates Cell Migration through Inhibition of PAI-1 Expression

2005 ◽  
Vol 25 (24) ◽  
pp. 10853-10862 ◽  
Author(s):  
Gilles Buchwalter ◽  
Christian Gross ◽  
Bohdan Wasylyk
Keyword(s):  
Cell Migration ◽  
Ternary Complex ◽  
Target Genes ◽  
Serum Response Factor ◽  
Plasminogen Activator Inhibitor ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Serum Response ◽  
Ternary Complex Factor ◽  
Pai 1

ABSTRACT Net, Elk-1, and Sap-1 are members of the ternary complex factor (TCF) subfamily of Ets transcription factors. They form ternary complexes with serum response factor (SRF) on serum response elements of immediate early genes such as c-fos and egr-1 and mediate responses to growth factors and mitogen-activated protein kinase signaling. Although the TCFs have been extensively studied as intermediates in signaling cascades, surprisingly little is known about their different target genes and physiological functions. We report that Net homozygous mutant mouse embryonic fibroblasts have a defect in cell migration. This defect results at least in part from increased expression of plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor (serpin) that controls extracellular proteolysis and cell matrix adhesion. The defect in cell migration can be reverted by the addition of a PAI-1 blocking antibody. Net represses PAI-1 promoter activity and binds to a specific region of the promoter containing Ets binding sites in the absence of SRF. We conclude that Net is a negative regulator of PAI-1 expression and is thereby involved in cell migration.

scholarly journals Phosphorylation-dependent formation of a quaternary complex at the c-fos SRE.

1996 ◽  
Vol 16 (3) ◽  
pp. 1094-1102 ◽  
Author(s):  
H Gille ◽  
M Kortenjann ◽  
T Strahl ◽  
P E Shaw
Keyword(s):  
Ternary Complex ◽  
Serum Response Factor ◽  
Multicomponent Complex ◽  
Intermolecular Association ◽  
Quaternary Complex ◽  
In Vivo Footprinting ◽  
Serum Response ◽  
Ternary Complex Factor

The rapid and transient induction of the human proto-oncogene c-fos in response to a variety of stimuli depends on the serum responses element (SRE). In vivo footprinting experiments show that this promoter element is bound by a multicomponent complex including the serum response factor (SRF) and a ternary complex factor such as Elk-1. SRF is thought to recruit a ternary complex factor monomer into an asymmetric complex. In this report, we describe a quaternary complex over the SRE which, in addition to an SRF dimer, contains two Elk-1 molecules. Its formation at the SRE is strictly dependent on phosphorylation of S-383 in the Elk-1 regulatory domain and appears to involve a weak intermolecular association between the two Elk-1 molecules. The influence of mutations in Elk-1 on quaternary complex formation in vitro correlates with their effect on the induction of c-fos reporter expression in response to mitogenic stimuli in vivo.

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