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Regulation of the protein stability of POSH and MLK family

Chunyan Wang1, Yang Tao, Yaqing Wang

  • 1Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

Protein & Cell
|January 5, 2011
PubMed

Insights

Scaffold protein POSH regulates JNK pathway activation and cell death by controlling protein stability. Its N-terminal region is key, and its apoptosis-inducing ability correlates with stability and MLK binding.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The c-Jun N-terminal kinase (JNK) pathway is crucial for initiating cell death.
  • Scaffold proteins like POSH (Plenty of SH3's) organize JNK pathway components for efficient activation.
  • Recent findings indicate that POSH and MLK (mixed-lineage kinase) protein levels are controlled by protein stability.

Purpose of the Study:

  • To investigate the role of POSH protein domains in stability and JNK pathway-mediated cell death.
  • To explore the relationship between POSH stability, MLK binding, and apoptosis induction.
  • To examine the effect of dominant-negative c-Jun on MLK stability.

Main Methods:

  • Site-directed mutagenesis to generate POSH mutants.
  • Analysis of protein stability and expression levels.
  • Assessment of JNK pathway activation and apoptosis.
  • Co-immunoprecipitation assays to study protein interactions.

Main Results:

  • The N-terminal half of POSH is essential for its stability regulation and its ability to induce cell death upon overexpression.
  • POSH-induced apoptosis is directly correlated with its protein stability and its binding affinity to MLK proteins.
  • MLK family protein stability, similar to POSH, depends on JNK pathway activation.
  • Dominant-negative c-Jun was found to decrease MLK stability, suggesting therapeutic potential.

Conclusions:

  • The N-terminus of POSH is a critical determinant of its stability and function in JNK-mediated apoptosis.
  • POSH stability and MLK binding are key factors for its apoptotic activity.
  • The findings suggest that peptides derived from dominant-negative c-Jun could be developed as therapeutic agents targeting MLK stability.

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