The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression

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Updated: Aug 16, 2026

Examining BCL-2 Family Function with Large Unilamellar Vesicles
08:35

Examining BCL-2 Family Function with Large Unilamellar Vesicles

Published on: October 5, 2012

A K Samraj1, C Stroh, U Fischer

  • 1Institute of Molecular Medicine, University of Düsseldorf, Germany.

Oncogene
|August 24, 2005
PubMed

Insights

The lymphoid-specific Src kinase p56(Lck) regulates mitochondrial apoptosis. Lck deficiency confers drug resistance by blocking Bak expression, while Lck re-expression restores sensitivity via Bak activation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Src family kinases (SFKs) are crucial in cellular signaling.
  • p56(Lck) is a lymphoid-specific SFK involved in T-cell function.
  • The role of Lck in apoptosis, particularly the mitochondrial pathway, is not fully understood.

Purpose of the Study:

  • To investigate the role of p56(Lck) in drug-induced apoptosis.
  • To elucidate the specific pathway through which Lck influences apoptosis.
  • To identify downstream targets of Lck in the apoptotic process.

Main Methods:

  • Utilized Lck-deficient T cells and Lck-reconstituted cells.
  • Assessed sensitivity to anticancer drugs and death receptor-mediated apoptosis.
  • Analyzed mitochondrial cytochrome c release, caspase activation, and Bcl-2 protein expression (Bak).
  • Investigated the transcriptional regulation of Bak by Lck.
  • Performed in vitro assays using truncated Bid to assess Bak activation.

Main Results:

  • Lck-deficient T cells exhibited complete resistance to anticancer drugs but normal sensitivity to death receptors.
  • Re-expression of Lck restored drug sensitivity, triggering cytochrome c release and caspase activation.
  • Lck-mediated sensitization was independent of classical T-cell signaling but critically involved Bak.
  • Lck deficiency resulted in absent Bak expression; Lck re-expression induced Bak transcription and activation.
  • Lck-expressing cells showed enhanced Bak-mediated cytochrome c release upon Bid activation.

Conclusions:

  • p56(Lck) plays a critical role in regulating the mitochondrial apoptosis pathway, specifically in response to anticancer drugs.
  • Lck acts as a sentinel in drug resistance by transcriptionally inducing the expression and activation of the proapoptotic protein Bak.
  • This study reveals a novel pathway for Src kinases in regulating Bcl-2 family proteins and offers potential therapeutic targets for overcoming drug resistance.

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