Functional inactivation of a transcriptional corepressor by a signaling kinase

Nat Struct Biol. 2003 Aug;10(8):622-8. doi: 10.1038/nsb957.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases
  • Amino Acid Substitution
  • Binding Sites
  • Cell Line, Tumor
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • Female
  • Humans
  • In Vitro Techniques
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Serine / chemistry
  • Signal Transduction
  • Two-Hybrid System Techniques
  • p21-Activated Kinases

Substances

  • DNA-Binding Proteins
  • Phosphoproteins
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Serine
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • PAK1 protein, human
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases