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p66Shc-dependent apoptosis requires Lck and CamKII activity

Laura Patrussi1, Nico Giommoni, Michela Pellegrini

  • 1Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy. patrussi2@unisi.it

Apoptosis : an International Journal on Programmed Cell Death
|October 11, 2011
PubMed

Insights

p66Shc promotes T-cell apoptosis by increasing reactive oxygen species (ROS) and impairing calcium (Ca2+) homeostasis. This study reveals Lck kinase is crucial for p66Shc

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • p66Shc enhances mitochondrial reactive oxygen species (ROS) production, promoting T-cell apoptosis.
  • p66Shc induces apoptosis via mitochondrial dysfunction and impaired calcium (Ca2+) homeostasis.
  • Lck kinase is implicated in T-cell apoptosis triggered by various stimuli.

Purpose of the Study:

  • To investigate the role of Lck kinase in p66Shc-mediated T-cell apoptosis.
  • To elucidate the molecular mechanisms linking p66Shc, Lck, and T-cell apoptosis.

Main Methods:

  • Utilized Jurkat T cells overexpressing p66Shc with and without Lck expression.
  • Assessed apoptotic responses to elevated intracellular calcium levels ([Ca2+]c).
  • Investigated p66Shc phosphorylation at serine 36 (S36) and the involvement of CaMKII.

Main Results:

  • Lck deficiency impaired p66Shc-dependent apoptosis in response to increased [Ca2+]c.
  • Lck kinase activity is required for p66Shc phosphorylation at S36, a critical proapoptotic event.
  • p66Shc-induced mitochondrial dysfunction, altered Ca2+ homeostasis, and S36 phosphorylation depend on CaMKII activity.

Conclusions:

  • Lck is essential for p66Shc-mediated T-cell apoptosis.
  • Calcium signaling activates CaMKII, which then promotes Lck-dependent p66Shc phosphorylation.
  • This phosphorylation cascade leads to synergistic mitochondrial dysfunction and Ca2+ imbalance, driving T-cell apoptosis.

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