Phosphorylation of Krüppel-like Factor 3 (KLF3/BKLF) and C-terminal Binding Protein 2 (CtBP2) by Homeodomain-interacting Protein Kinase 2 (HIPK2) Modulates KLF3 DNA Binding and Activity

Krüppel-like factor 3 (KLF3/BKLF), a member of the Krüppel-like factor (KLF) family of transcription factors, is a widely expressed transcriptional repressor with diverse biological roles. Although there is considerable understanding of the molecular mechanisms that allow KLF3 to silence the activit...

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Published in:The Journal of biological chemistry 2015-03, Vol.290 (13), p.8591-8605
Main Authors: Dewi, Vitri, Kwok, Alister, Lee, Stella, Lee, Ming Min, Tan, Yee Mun, Nicholas, Hannah R., Isono, Kyo-ichi, Wienert, Beeke, Mak, Ka Sin, Knights, Alexander J., Quinlan, Kate G.R., Cordwell, Stuart J., Funnell, Alister P.W., Pearson, Richard C.M., Crossley, Merlin
Format: Article
Language:English
Subjects:
Alcohol Oxidoreductases
Amino Acid Sequence
Animals
C-terminal Binding Protein (CtBP2)
Carrier Proteins - physiology
Chlorocebus aethiops
Co-Repressor Proteins
COS Cells
DNA - chemistry
DNA-Binding Proteins - metabolism
Electrophoretic Mobility Shift Assay
Gene Expression
Gene Regulation
Homeodomain-interacting Protein Kinase 2 (HIPK2)
Kruppel-like Factor (KLF)
Kruppel-like Factor 3 (KLF3/BKLF)
Kruppel-Like Transcription Factors - chemistry
Kruppel-Like Transcription Factors - metabolism
Mice
Molecular Sequence Data
NIH 3T3 Cells
Phosphoproteins - metabolism
Phosphorylation
Post-translational Modification (PTM)
Protein Binding
Protein Phosphorylation
Protein Processing, Post-Translational
Protein-Serine-Threonine Kinases - physiology
Transcription Regulation
Transcription, Genetic
Transcriptional Activation
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Summary:Krüppel-like factor 3 (KLF3/BKLF), a member of the Krüppel-like factor (KLF) family of transcription factors, is a widely expressed transcriptional repressor with diverse biological roles. Although there is considerable understanding of the molecular mechanisms that allow KLF3 to silence the activity of its target genes, less is known about the signal transduction pathways and post-translational modifications that modulate KLF3 activity in response to physiological stimuli. We observed that KLF3 is modified in a range of different tissues and found that the serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) can both bind and phosphorylate KLF3. Mass spectrometry identified serine 249 as the primary phosphorylation site. Mutation of this site reduces the ability of KLF3 to bind DNA and repress transcription. Furthermore, we also determined that HIPK2 can phosphorylate the KLF3 co-repressor C-terminal binding protein 2 (CtBP2) at serine 428. Finally, we found that phosphorylation of KLF3 and CtBP2 by HIPK2 strengthens the interaction between these two factors and increases transcriptional repression by KLF3. Taken together, our results indicate that HIPK2 potentiates the activity of KLF3. Background: Krüppel-like factor 3 (KLF3) is a transcriptional repressor with multiple biological roles. Results: Phosphorylation of KLF3 by homeodomain-interacting protein kinase 2 (HIPK2) promotes DNA binding and transcriptional repression. Conclusion: Signal transduction pathways mediated by HIPK2 control and direct KLF3 activity. Significance: Determining the pathways that control KLF3 function offers potential for regulating its activity for therapeutic benefit.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M115.638338