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Altered physical state of p210bcr-abl in tyrphostin AG957-treated K562 cells.

Abstract
AG957 is a tyrosine kinase antagonist which prior studies had shown inhibits p210bcr-abl tyrosine kinase activity and K562 chronic myelogenous leukemia cell growth. We report here the effects of AG957 on the physical state of p210bcr-abl and its signaling adapter molecules Shc and Grb2 in K562 cells. After exposure to AG957, the amount of tyrosine-phosphorylated native p210bcr-abl decreases, with the appearance of a high molecular weight (> 210 kDa) p210bcr-abl. This effect is seen after [32P]orthophosphate and [35S]methionine labeling. Material suggesting the involvement of p210bcr-abl in high molecular weight complexes also appears using anti-Shc, anti-Grb2 and anti-phosphotyrosine antibodies. AG957 also acts in vitro to shift native p210bcr-abl in anti-p210bcr-abl or anti-Grb2 immunoprecipitates to higher molecular weight forms under conditions where the drug can also act as an antagonist of p210bcr-abl autokinase activity. Incubation with dithiothreitol inhibits the appearance of > 210 kDa forms of p210bcr-abl in the in vitro reaction. These results leads to the hypothesis that AG957 does not act simply as a reversible tyrosine kinase antagonist, but can alter the normal amounts and physical associations of molecules important in tyrosine kinase signaling. These effects likely reflect covalent cross-links induced by the drug.
AuthorsG Kaur, E A Sausville
JournalAnti-cancer drugs (Anticancer Drugs) Vol. 7 Issue 8 Pg. 815-24 (Nov 1996) ISSN: 0959-4973 [Print] England
PMID8991184 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Benzylidene Compounds
  • Nitriles
  • Phosphorus Radioisotopes
  • Sulfur Radioisotopes
  • Tyrphostins
  • tyrphostin AG957
  • Fusion Proteins, bcr-abl
  • Serine Endopeptidases
  • glutamyl endopeptidase
Topics
  • Animals
  • Antibodies, Monoclonal
  • Benzylidene Compounds (pharmacology)
  • Blotting, Western
  • Cell Division (drug effects)
  • Fusion Proteins, bcr-abl (chemistry, metabolism)
  • Humans
  • Hydrolysis
  • Isotope Labeling
  • Mice
  • Molecular Weight
  • Nitriles (pharmacology)
  • Phosphorus Radioisotopes
  • Phosphorylation
  • Precipitin Tests
  • Serine Endopeptidases
  • Signal Transduction (drug effects)
  • Sulfur Radioisotopes
  • Tumor Cells, Cultured
  • Tyrphostins

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