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Selective interactions of transforming and normal abl proteins with ATP, tyrosine-copolymer substrates, and

M Anafi1, A Gazit, C Gilon

  • 1Lautenberg Center for Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel.

The Journal of Biological Chemistry
|March 5, 1992
PubMed

Insights

Transforming abl proteins exhibit higher affinity for ATP and substrates than normal abl. Tyrphostin blockers can distinguish between normal and transforming abl proteins, suggesting targeted leukemia therapies.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Normal c-Abl protein (p140c-abl) and transforming abl proteins (p160gag-abl, p185bcr-abl, p210bcr-abl) share catalytic sites but differ in N-terminal domains.
  • Previous research indicated transforming abl proteins have higher tyrosine kinase activity than normal abl proto-oncogene product.

Purpose of the Study:

  • To investigate the substrate affinities of transforming abl proteins compared to the normal abl protein.
  • To determine if protein tyrosine kinase blockers can differentiate between normal and transforming abl proteins.

Main Methods:

  • Assessed the binding affinity of p210bcr-abl and p160gag-abl to ATP and synthetic tyrosine-containing substrates.
  • Tested the ability of tyrphostin family protein tyrosine kinase blockers to discriminate between normal abl and transforming abl proteins from human and mouse sources.

Main Results:

  • p210bcr-abl and p160gag-abl demonstrated higher affinity for ATP and substrates than p140c-abl.
  • Tyrphostins successfully discriminated between normal and transforming abl proteins of both human and mouse origin.

Conclusions:

  • Higher affinities of transforming abl proteins for signal transducers may contribute to their oncogenic potential.
  • This study is the first to show oncogene products differ from homologous proto-oncogene products in substrate specificity.
  • The selectivity of tyrphostins suggests potential for developing specific abl kinase inhibitors for abl-associated leukemias.

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