Advertisement

Protein & Cell

, Volume 1, Issue 9, pp 871–878 | Cite as

Regulation of the protein stability of POSH and MLK family

  • Chunyan Wang
  • Yang Tao
  • Yaqing WangEmail author
  • Zhiheng XuEmail author
Research Article

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.

Keywords

the JNK pathway protein stability POSH MLK family and poptosis 

References

  1. Aletta, J.M., Shelanski, M.L., and Greene, L.A. (1989). Phosphorylation of the peripherin 58-kDa neuronal intermediate filament protein. Regulation by nerve growth factor and other agents. J Biol Chem 264, 4619–4627.Google Scholar
  2. Böck, B.C., Vacratsis, P.O., Qamirani, E., and Gallo, K.A. (2000). Cdc42-induced activation of the mixed-lineage kinase SPRK in vivo. Requirement of the Cdc42/Rac interactive binding motif and changes in phosphorylation. J Biol Chem 275, 14231–14241.CrossRefGoogle Scholar
  3. Coso, O.A., Chiariello, M., Yu, J.C., Teramoto, H., Crespo, P., Xu, N., Miki, T., and Gutkind, J.S. (1995). The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81, 1137–1146.CrossRefGoogle Scholar
  4. Davis, R.J. (2000). Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252.CrossRefGoogle Scholar
  5. Figueroa, C., Tarras, S., Taylor, J., and Vojtek, A.B. (2003). Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex. J Biol Chem 278, 47922–47927.CrossRefGoogle Scholar
  6. Kukekov, N.V., Xu, Z., and Greene, L.A. (2006). Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic activation of JNKs. J Biol Chem 281, 15517–15524.CrossRefGoogle Scholar
  7. Lei, K., and Davis, R.J. (2003). JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A 100, 2432–2437.CrossRefGoogle Scholar
  8. Liu, J., and Lin, A. (2005). Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15, 36–42.CrossRefGoogle Scholar
  9. Tapon, N., Nagata, K., Lamarche, N., and Hall, A. (1998). A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways. EMBO J 17, 1395–1404.CrossRefGoogle Scholar
  10. Xu, Z., Maroney, A.C., Dobrzanski, P., Kukekov, N.V., and Greene, L. A. (2001). The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol 21, 4713–4724.CrossRefGoogle Scholar
  11. Xu, Z., Kukekov, N.V., and Greene, L.A. (2003). POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J 22, 252–261.CrossRefGoogle Scholar
  12. Xu, Z., Kukekov, N., and Greene, L. (2005). A stability-based selfamplifying feed forward loop mechanism for regulation of the apoptotic JNK pathway. Mol Cell Biol 25, 9949–9959.CrossRefGoogle Scholar
  13. Xu, Z., Sproul, A., Wang, W.Y., Kukekov, N., and Greene, L.A. (2006). Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. J Biol Chem 281, 303–312.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina

Personalised recommendations