Phosphorylation represses Ets-1 DNA binding by reinforcing autoinhibition
Open accessAbstract
Phosphorylation of transcription factors is a key link between cell signaling and the control of gene expression. Here we report that phosphorylation regulates DNA binding of the Ets-1 transcription factor by reinforcing an autoinhibitory mechanism. Quantitative DNA-binding assays show that calcium-dependent phosphorylation inhibits Ets-1 DNA binding 50-fold. The four serines that mediate this inhibitory effect are distant from the DNA-binding domain but near structural elements required for autoinhibition. Mutational analyses demonstrate that an intact inhibitory module is required for phosphorylation-dependent regulation. Partial proteolysis studies indicate that phosphorylation stabilizes an inhibitory conformation. These findings provide a structural mechanism for phosphorylation-dependent inhibition of Ets-1 DNA binding and demonstrate a new function for inhibitory modules as structural mediators of negative signaling events.
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ETS1 autoinhibition is reinforced by phosphorylation and counteracted by protein partnerships such as those with RUNX1 and PAX5.
“As discussed below, ETS1 autoinhibition is reinforced by phosphorylation (74, 75) and counteracted by protein partnerships, such as those with RUNX1 (also termed AML1/CBFα2) and PAX5.”
From Genomic and biochemical insights into the specificity of ETS transcription factors (2011) · cites this paper as [75]
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References 60 · Cited by 152
- Authors
- Cowley, D. O., & Graves, B. J.
- Affiliations
- University of Utah (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-02-01
- Volume
- 14
- Issue
- 3
- Pages
- 366-376
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316366
- OpenAlex
- W2131713324
- Cited by
- 152
- References
- 60
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 8 · 2013: 7 · 2012: 6
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Huntsman Cancer Institute
- National Institutes of Health
- National Cancer Institute (CA24014)
- National Institute of General Medical Sciences (GM 38663, R01GM038663)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-07491, T32HD007491)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- ETS1, transcription factor phosphorylation, DNA binding inhibition, autoinhibition, calcium-dependent phosphorylation, serine phosphorylation, protein conformational stability, transcriptional regulation, negative signaling
- MeSH terms
- Amino Acid Sequence, Cell Extracts, DNA, DNA-Binding Proteins, Humans, Models, Biological, Molecular Sequence Data, Phosphorylation, Phosphoserine, Proto-Oncogene Proteins, T-Lymphocytes, Transcription Factors, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Calcium-Calmodulin-Dependent Protein Kinases, Proto-Oncogene Proteins c-ets, Proto-Oncogene Protein c-ets-1, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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