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.
Yi
Ping
P
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Feng
Qin
Q
Amazit
Larbi
L
Lonard
David M
DM
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
O'Malley
Bert W
BW
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D047628:Estrogen Receptor alpha; D004967:Estrogens; D051548:Histone Acetyltransferases; D007527:Isoenzymes; D056921:Nuclear Receptor Coactivator 3; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C; D021122:Protein Subunits; D015534:Trans-Activators; D014157:Transcription Factors; D000099221:Protein Kinase C zeta; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse