Functional inactivation of a transcriptional corepressor by a signaling kinase

  title={Functional inactivation of a transcriptional corepressor by a signaling kinase},
  author={Christopher J. Barnes and Ratna K. Vadlamudi and Sandip K. Mishra and Raymond H. Jacobson and Feng Li and Rakesh Kumar},
  journal={Nature Structural Biology},
The C-terminal binding protein 1 (CtBP) is a ubiquitous corepressor linking the recruitment of DNA- and histone-modifying proteins to sequence-specific DNA-binding proteins and facilitating gene regulation during development and oncogenesis. We describe here the binding, phosphorylation and functional regulation of CtBP by the p21-activated kinase 1 (Pak1). Pak1 phosphorylates CtBP selectively on Ser158 within a putative regulatory loop, triggering CtBP cellular redistribution and blocking CtBP… 

The Transcriptional Co-Repressor C-Terminal Binding Protein (CtBP) Associates with Centrosomes During Mitosis

It is shown by immunofluorescence laser-scanning confocal microscopy that in mitotic cells a species of CtBP becomes associated with the centrosomes at the onset of prophase and then throughout mitosis, which may explain how a nuclear co-repressor of transcription can exert a regulatory effect on the Golgi complex at a specific stage of the cell cycle.

C-terminal binding proteins: central players in development and disease

Although recent efforts have characterized the essential involvement of CtBPs in promoting cellular survival, the dysregulation of Ct BPs in both neurodegenerative disease and cancers remains to be fully elucidated.

AMP-activated protein kinase phosphorylates CtBP1 and down-regulates its activity.

Inhibition of CtBP1 activity by Akt-mediated phosphorylation.

PAK1 and CtBP1 Regulate the Coupling of Neuronal Activity to Muscle Chromatin and Gene Expression

A molecular mechanism to account for the coordinated control of chromatin modifications and muscle gene expression by presynaptic neurons via a PAK1/CtBP1 pathway is revealed.

Signaling coupled epigenomic regulation of gene expression

Recent advances in signaling-dependent epigenomic regulation of gene transcription are discussed using a few representative cancer-relevant serine/threonine and tyrosine kinases and their interplay with chromatin remodeling factors in cancer cells.

C-terminal binding proteins: Emerging roles in cell survival and tumorigenesis

The evidence supporting a key role for CtBP proteins in cell survival is summarized, the known mechanisms of transcriptional control by CtBPs are described, and the multiplicity of intracellular signaling and transcriptional Control pathways with which they are known to be involved are reviewed.

Nuclear Speckle-Associated Protein Pnn/DRS Binds to the Transcriptional Corepressor CtBP and Relieves CtBP- Mediated Repression of the E-Cadherin Gene

Evidence is presented that pinin/DRS interacts with the known transcriptional corepressor CtBP1 and Pnn was capable of relieving the Ct BP1-mediated repression of E-cadherin promoter activity and this interaction may reflect the existence of coupling factors involved in CtBP-mediated transcriptional regulation and mRNA processing events.



A mechanism for Rb/p130-mediated transcription repression involving recruitment of the CtBP corepressor.

It is shown that both CtIP and CtBP can efficiently repress transcription when recruited to a promoter by the Gal4 DNA binding domain, thereby identifying them as corepressor proteins.

Nuclear Localization and Cell Cycle-specific Expression of CtIP, a Protein That Associates with the BRCA1 Tumor Suppressor*

The results indicate that CtIP can potentially modulate the functions ascribed to BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control.

Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1

The results indicate that FLNa may be essential for Pak1-induced cytoskeletal reorganization and that the two-way regulatory interaction between Pak1 and FLNa might contribute to the local stimulation of Pak1 activity and its targets in cytoskeleton structures.

Regulation of Corepressor Function by Nuclear NADH

It is proposed that this ability to detect changes in nuclear NAD+/NADH ratio allows CtBP to serve as a redox sensor for transcription.

Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation.

Results suggest that interaction of CtBP with the E1A proteins may play a critical role in adenovirus replication and oncogenic transformation.

C-Terminal Binding Protein Is a Transcriptional Repressor That Interacts with a Specific Class of Vertebrate Polycomb Proteins

The results are discussed in terms of a model that brings together PcG-mediated repression and repression systems that require corepressors such as CtBP, and it is shown that CtBP is a transcriptional repressor.

P21‐activated kinase‐1 phosphorylates and transactivates estrogen receptor‐α and promotes hyperplasia in mammary epithelium

A novel role for the Pak1–ER pathway in promoting hyperplasia in mammary epithelium is revealed and inhibition of Pak1 kinase activity by a dominant‐negative fragment or by short interference RNA markedly reduced the estrogen receptor‐α (ER) transactivation functions.