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.
Welch
P J
PJ
Department of Biology, University of California, San Diego, La Jolla 92093-0116.
Wang
J Y
JY
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D002453:Cell Cycle; D002467:Cell Nucleus / Q000201:enzymology; D004789:Enzyme Activation; D006131:Growth Inhibitors / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D016196:S Phase; D015534:Trans-Activators; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D006133:Growth Substances; D009687:Nuclear Proteins; D009842:Oligopeptides; D016160:Retinoblastoma Protein; D015534:Trans-Activators; C037841:tyrosyl-alanyl-glycine; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl