Functional inactivation of a transcriptional corepressor by a signaling kinase

Christopher J. Barnes, Ratna K. Vadlamudi, Sandip K. Mishra, Raymond H. Jacobson, Feng Li, Rakesh Kumar

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

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 corepressor functions. A S158A substitution in CtBP or Pak1 knockdown by short interference RNA blocked CtBP phosphorylation, redistribution and attenuation of CtBP corepressor functions in reporter and chromatin assays. In the presence of NADH, Pak1 superphosphorylates CtBP and inhibits CtBP dehydrogenase activity, suggesting that preferential phosphorylation of active CtBP may alter secondary structures and influence both enzymatic and corepressor functions. Pak1 regulation of CtBP represents a new model of corepressor regulation whereby cellular signaling cascades may influence gene expression in mammalian cells.

Original languageEnglish (US)
Pages (from-to)622-628
Number of pages7
JournalNature Structural Biology
Volume10
Issue number8
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

Fingerprint Dive into the research topics of 'Functional inactivation of a transcriptional corepressor by a signaling kinase'. Together they form a unique fingerprint.

Cite this