Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Breast Neoplasms, Cell Line, Endoplasmic Reticulum, Estrogen Receptor alpha, Estrogens, Female, Gene Expression Regulation, Histone Acetyltransferases, Humans, Isoenzymes, Mice, Molecular Sequence Data, Nuclear Receptor Coactivator 3, Phosphorylation, Proteasome Endopeptidase Complex, Protein Kinase C, Protein Subunits, Sequence Alignment, Trans-Activators, Transcription Factors
Amino Acid Sequence, Animals, Breast Neoplasms, Cell Line, Endoplasmic Reticulum, Estrogen Receptor alpha, Estrogens, Female, Gene Expression Regulation, Histone Acetyltransferases, Humans, Isoenzymes, Mice, Molecular Sequence Data, Nuclear Receptor Coactivator 3, Phosphorylation, Proteasome Endopeptidase Complex, Protein Kinase C, Protein Subunits, Sequence Alignment, Trans-Activators, Transcription Factors
Mol. Cell
Date: Feb. 29, 2008
PubMed ID: 18313384
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