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TRAIL/MEKK4/p38/HSP27/Akt survival network is biphasically modulated by the Src/CIN85/c-Cbl complex

Jina Kim1, Dongxu Kang, Bo K Sun

  • 1Institute for Cancer Research, College of Medicine, Yonsei University, Seoul, Republic of Korea.

Cellular Signalling
|October 23, 2012
PubMed

Insights

The Src/c-Cbl interacting protein of 85kDa (CIN85) complex modulates the MEKK4/p38/heat shock protein (HSP27)/Akt survival network. Phosphorylated p38/HSP27 and CIN85 act as biphasic modulators to control cell fate during apoptotic stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mitogen-activated protein kinase/extracellular signal-related kinase 4 (MEKK4) activates p38, influencing Akt activity during tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment.
  • The Src/c-Cbl interacting protein of 85kDa (CIN85)/c-Cbl complex's role in modulating this survival network requires further investigation.

Purpose of the Study:

  • To investigate how the CIN85/c-Cbl complex modulates the TRAIL-induced MEKK4/p38/heat shock protein (HSP27)/Akt survival network.
  • To elucidate the role of phosphorylated p38/HSP27 and CIN85 in determining cell fate under apoptotic stress.

Main Methods:

  • Investigated the correlation between Akt activation and p38/HSP27 phosphorylation during TRAIL treatment.
  • Analyzed the effect of curcumin and TRAIL cotreatment on p38/HSP27 phosphorylation and cell death.
  • Examined the interaction between CIN85 and MEKK4 during TRAIL incubation.

Main Results:

  • TRAIL-induced Akt activation correlated with p38/HSP27 phosphorylation.
  • Curcumin and TRAIL cotreatment further increased p38/HSP27 phosphorylation, leading to significant apoptotic cell death.
  • Increased CIN85 interaction with MEKK4 during late TRAIL incubation suggested a protective role of sustained p38/HSP27 phosphorylation, which was overcome by curcumin, inducing cell death.

Conclusions:

  • Phosphorylated p38/HSP27 acts as a biphasic modulator of cell survival and death.
  • CIN85 plays a crucial role in linking cell survival pathways to cell death decisions.
  • The interplay between phosphorylated p38/HSP27 and CIN85 determines cellular response to apoptotic stimuli like TRAIL.

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