Rack1 Protects N-terminal Phosphorylated c-Jun From Fbw7-mediated Degradation

Oncogene. 2012 Apr 5;31(14):1835-44. doi: 10.1038/onc.2011.369. Epub 2011 Aug 22.

Abstract

The c-Jun transcription factor is a highly unstable oncoprotein. Several ubiquitin ligases mediate c-Jun degradation. However, c-Jun can be stabilized once it is phosphorylated at the N-terminus by c-Jun N-terminal kinases (JNKs) or other protein kinases. This phosphorylation decreases c-Jun ubiquitination and degradation. The underlying mechanism for this phenomenon is still unknown. Here, we show that receptor for activated C-kinase 1 (Rack1) can bind with c-Jun and ubiquitin ligase Fbw7 to form a complex. When c-Jun is phosphorylated at the N-terminus, c-Jun is released from the complex and cannot be ubiquitinated by Fbw7, which leads to increased stabilization and accumulation of c-Jun. These results reveal that Rack1 has a very important role in tumorigenesis by maintaining the stability of c-Jun that has been phosphorylated at its N-terminus by JNKs or other kinases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • GTP-Binding Proteins / physiology*
  • Gene Knockdown Techniques
  • Mice
  • Neoplasm Proteins / physiology*
  • Phosphorylation
  • Protein Stability
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / physiology*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-jun
  • RACK1 protein, human
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • Ubiquitin-Protein Ligases
  • GTP-Binding Proteins