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A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle.

The ubiquitously expressed c-Abl tyrosine kinase is localized to the nucleus and binds to DNA. The DNA binding activity is regulated by cdc2-mediated phosphorylation, suggesting a cell cycle function for c-Abl. Here we show that the tyrosine kinase activity of nuclear c-Abl is regulated in the cell cycle through a specific interaction with the retinoblastoma protein (RB). A domain in the C-terminus of RB, outside of the A/B pocket, binds to the ATP-binding lobe of the c-Abl tyrosine kinase, resulting in kinase inhibition. The RB-c-Abl interaction is not affected by the viral oncoproteins that bind to RB. Hyperphosphorylation of RB correlates with release of c-Abl and activation of the tyrosine kinase in S phase cells. The nuclear c-Abl tyrosine kinase can enhance transcription, and this activity is inhibited by RB. Nuclear c-Abl is an S phase-activated tyrosine kinase that may participate directly in the regulation of transcription.

Pubmed ID: 8242749

Authors

  • Welch PJ
  • Wang JY

Journal

Cell

Publication Data

November 19, 1993

Associated Grants

  • Agency: NCI NIH HHS, Id: CA43054
  • Agency: NCI NIH HHS, Id: CA58320

Mesh Terms

  • Adenosine Triphosphate
  • Amino Acid Sequence
  • Binding Sites
  • Cell Cycle
  • Cell Nucleus
  • Enzyme Activation
  • Growth Inhibitors
  • Growth Substances
  • Humans
  • In Vitro Techniques
  • Molecular Sequence Data
  • Nuclear Proteins
  • Oligopeptides
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-abl
  • Retinoblastoma Protein
  • S Phase
  • Trans-Activators
  • Tumor Cells, Cultured