Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1

Mol Cell. 2008 Feb 29;29(4):465-76. doi: 10.1016/j.molcel.2007.12.030.


SRC-3/AIB1 is a steroid receptor coactivator with potent growth-promoting activity, and its overexpression is sufficient to induce tumorigenesis. Previous studies indicate that the cellular level of SRC-3 is tightly regulated by both ubiquitin-dependent and ubiquitin-independent proteasomal degradation pathways. Atypical protein kinase C (aPKC) is frequently overexpressed in cancers. In the present study, we show that aPKC phosphorylates and specifically stabilizes SRC-3 in a selective ER-dependent manner. We further demonstrate that an acidic residue-rich region in SRC-3 is an important determinant for aPKC-mediated phosphorylation and stabilization. The mechanism of the aPKC-mediated stabilization appears due to a decreased interaction between SRC-3 and the C8 subunit of the 20S core proteasome, thus preventing SRC-3 degradation. Our results demonstrate a potent signaling mechanism for regulating SRC-3 levels in cells by coordinate enzymatic inhibition of both ubiquitin-dependent and ubiquitin-independent proteolytic pathways.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line
  • Endoplasmic Reticulum / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Female
  • Gene Expression Regulation
  • Histone Acetyltransferases / chemistry
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Mice
  • Molecular Sequence Data
  • Nuclear Receptor Coactivator 3
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Sequence Alignment
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Estrogen Receptor alpha
  • Estrogens
  • Isoenzymes
  • Protein Subunits
  • Trans-Activators
  • Transcription Factors
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3
  • protein kinase C zeta
  • Protein Kinase C
  • Proteasome Endopeptidase Complex