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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Published on: September 18, 2013

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The oncogenic tyrosine kinase Lyn impairs the pro-apoptotic function of Bim

Lazaro E Aira1, Elodie Villa1, Pascal Colosetti1

  • 1Université Côte d'Azur, INSERM, C3M, Nice, France.

Oncogene
|February 3, 2018
PubMed

Insights

The tyrosine kinase Lyn phosphorylates the pro-apoptotic protein Bim, inhibiting its function. This Lyn-dependent phosphorylation enhances Bim

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Serine/Threonine phosphorylation modulates the pro-apoptotic function of the BH3-only protein Bim.
  • The role of tyrosine phosphorylation in regulating Bim's function and apoptosis remains unexplored.
  • The tyrosine kinase Lyn has previously demonstrated anti-apoptotic properties.

Purpose of the Study:

  • To investigate the potential tyrosine phosphorylation of Bim by the Src family kinase Lyn.
  • To determine the impact of tyrosine phosphorylation on Bim's pro-apoptotic activity and the mitochondrial pathway.
  • To elucidate the mechanism by which Lyn regulates Bim and apoptosis.

Main Methods:

  • Analysis of Bim tyrosine phosphorylation sites.
  • Assessment of Lyn's kinase activity towards Bim.
  • Co-immunoprecipitation assays to study protein interactions.
  • Mitochondrial outer membrane permeabilization assays.
  • Apoptosis assays.

Main Results:

  • Bim is phosphorylated on tyrosine residues 92 and 161 by the tyrosine kinase Lyn.
  • Lyn-mediated tyrosine phosphorylation of Bim inhibits its pro-apoptotic function.
  • Tyrosine phosphorylation increases Bim's interaction with anti-apoptotic proteins like Bcl-xL.
  • This interaction limits mitochondrial outer membrane permeabilization and subsequent apoptosis.

Conclusions:

  • Lyn directly phosphorylates Bim on specific tyrosine residues, thereby inhibiting apoptosis.
  • This mechanism involves enhanced binding of Bim to anti-apoptotic Bcl-2 family members.
  • The oncogenic tyrosine kinase Lyn negatively regulates the mitochondrial apoptotic pathway, potentially contributing to cancer cell transformation and chemoresistance.

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