Regulation of the protein stability of POSH and MLK family

Protein Cell. 2010 Sep;1(9):871-8. doi: 10.1007/s13238-010-0111-1. Epub 2010 Oct 7.

Abstract

Sequential activation of the JNK pathway components, including Rac1/Cdc42, MLKs (mixed-lineage kinases), MKK4/7 and JNKs, plays a required role in many cell death paradigms. Those components are organized by a scaffold protein, POSH (Plenty of SH3's), to ensure the effective activation of the JNK pathway and cell death upon apoptotic stimuli. We have shown recently that the expression of POSH and MLK family proteins are regulated through protein stability. By generating a variety of mutants, we provide evidence here that the Nterminal half of POSH is accountable for its stability regulation and its over-expression-induced cell death. In addition, POSH's ability to induce apoptosis is correlated with its stability as well as its MLK binding ability. MLK family's stability, like that of POSH, requires activation of JNKs. However, we were surprised to find out that the widely used dominant negative (d/n) form of c-Jun could down-regulate MLK's stability, indicating that peptide from d/n c-Jun can be potentially developed into a therapeutical drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis / physiology
  • Base Sequence
  • Cell Line
  • DNA Primers / genetics
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • PC12 Cells
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Stability
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / physiology
  • Transfection
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA Primers
  • Mutant Proteins
  • Nuclear Proteins
  • Peptide Fragments
  • Recombinant Proteins
  • Sh3rf1 protein, rat
  • Ubiquitin-Protein Ligases
  • seven in absentia proteins
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases