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. 2010 Oct 7;1(9):871–878. doi: 10.1007/s13238-010-0111-1

Regulation of the protein stability of POSH and MLK family

Chunyan Wang 1, Yang Tao 1, Yaqing Wang 1,✉, Zhiheng Xu 1,✉
PMCID: PMC4875233  PMID: 21203929

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

Contributor Information

Yaqing Wang, Email: wangyaqing@genetics.ac.cn.

Zhiheng Xu, Email: zhxu@genetics.ac.cn.

References

  1. Aletta J.M., Shelanski M.L., Greene L.A. Phosphorylation of the peripherin 58-kDa neuronal intermediate filament protein. Regulation by nerve growth factor and other agents. J Biol Chem. 1989;264:4619–4627. [PubMed] [Google Scholar]
  2. Böck B.C., Vacratsis P.O., Qamirani E., Gallo K.A. 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. 2000;275:14231–14241. doi: 10.1074/jbc.275.19.14231. [DOI] [PubMed] [Google Scholar]
  3. Coso O.A., Chiariello M., Yu J.C., Teramoto H., Crespo P., Xu N., Miki T., Gutkind J.S. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995;81:1137–1146. doi: 10.1016/S0092-8674(05)80018-2. [DOI] [PubMed] [Google Scholar]
  4. Davis R.J. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–252. doi: 10.1016/S0092-8674(00)00116-1. [DOI] [PubMed] [Google Scholar]
  5. Figueroa C., Tarras S., Taylor J., Vojtek A.B. Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex. J Biol Chem. 2003;278:47922–47927. doi: 10.1074/jbc.M307357200. [DOI] [PubMed] [Google Scholar]
  6. Kukekov N.V., Xu Z., Greene L.A. Direct interaction of the molecular scaffolds POSH and JIP is required for apoptotic activation of JNKs. J Biol Chem. 2006;281:15517–15524. doi: 10.1074/jbc.M601056200. [DOI] [PubMed] [Google Scholar]
  7. Lei K., Davis R.J. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A. 2003;100:2432–2437. doi: 10.1073/pnas.0438011100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Liu J., Lin A. Role of JNK activation in apoptosis: a double-edged sword. Cell Res. 2005;15:36–42. doi: 10.1038/sj.cr.7290262. [DOI] [PubMed] [Google Scholar]
  9. Tapon N., Nagata K., Lamarche N., Hall A. A new rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-kappaB signalling pathways. EMBO J. 1998;17:1395–1404. doi: 10.1093/emboj/17.5.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Xu Z., Maroney A.C., Dobrzanski P., Kukekov N.V., Greene L. A. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol. 2001;21:4713–4724. doi: 10.1128/MCB.21.14.4713-4724.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Xu Z., Kukekov N.V., Greene L.A. POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J. 2003;22:252–261. doi: 10.1093/emboj/cdg021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Xu Z., Kukekov N., Greene L. A stability-based selfamplifying feed forward loop mechanism for regulation of the apoptotic JNK pathway. Mol Cell Biol. 2005;25:9949–9959. doi: 10.1128/MCB.25.22.9949-9959.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Xu Z., Sproul A., Wang W.Y., Kukekov N., Greene L.A. Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. J Biol Chem. 2006;281:303–312. doi: 10.1074/jbc.M509060200. [DOI] [PubMed] [Google Scholar]

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