Essential Phosphatases and a Phospho-Degron Are Critical for Regulation of SRC-3/AIB1 Coactivator Function and Turnover

SRC-3/AIB1 is a master growth coactivator and oncogene, and phosphorylation activates it into a powerful coregulator. Dephosphorylation is a potential regulatory mechanism for SRC-3 function, but the identity of such phosphatases remains unexplored. Herein, we report that, using functional genomic s...

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Bibliographic Details
Published in:Molecular cell 2008-09, Vol.31 (6), p.835-849
Main Authors: Li, Chao, Liang, Yao-Yun, Feng, Xin-Hua, Tsai, Sophia Y., Tsai, Ming-Jer, O'Malley, Bert W.
Format: Article
Language:English
Subjects:
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Gene Expression Regulation
Genome - genetics
HeLa Cells
Humans
Nuclear Receptor Coactivator 3
Phosphoprotein Phosphatases - metabolism
Phosphoproteins - metabolism
Phosphoric Monoester Hydrolases - metabolism
Phosphorylation
Phosphoserine - metabolism
Proteasome Endopeptidase Complex - metabolism
Protein Binding
Protein Phosphatase 1 - metabolism
Protein Phosphatase 2 - metabolism
PROTEINS
Receptors, Estrogen - metabolism
RNA, Small Interfering - metabolism
Signal Transduction
SIGNALING
Thermodynamics
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
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Summary:SRC-3/AIB1 is a master growth coactivator and oncogene, and phosphorylation activates it into a powerful coregulator. Dephosphorylation is a potential regulatory mechanism for SRC-3 function, but the identity of such phosphatases remains unexplored. Herein, we report that, using functional genomic screening of human Ser/Thr phosphatases targeting SRC-3's known phosphorylation sites, the phosphatases PDXP, PP1, and PP2A were identified to be key negative regulators of SRC-3 transcriptional coregulatory activity in steroid receptor signalings. PDXP and PP2A dephosphorylate SRC-3 and inhibit its ligand-dependent association with estrogen receptor. PP1 stabilizes SRC-3 protein by blocking its proteasome-dependent turnover through dephosphorylation of two previously unidentified phosphorylation sites (Ser101 and S102) required for activity. These two sites are located within a degron of SRC-3 and are primary determinants of SRC-3 turnover. Moreover, PP1 regulates the oncogenic cell proliferation and invasion functions of SRC-3 in breast cancer cells.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2008.07.019