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

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

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

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.

PMID:
18313384
PMCID:
PMC2293272
DOI:
10.1016/j.molcel.2007.12.030
[Indexed for MEDLINE]
Free PMC Article

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