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Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and

Chao Li1, Yao-Yun Liang, Xin-Hua Feng

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

Molecular Cell
|October 17, 2008
PubMed

Insights

Researchers identified phosphatases PDXP, PP1, and PP2A as key negative regulators of SRC-3 (Steroid Receptor Coactivator-3) activity. These phosphatases dephosphorylate SRC-3, impacting its function in cancer cell proliferation and invasion.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • SRC-3 (Steroid Receptor Coactivator-3)/AIB1 is a crucial growth coactivator and oncogene activated by phosphorylation.
  • Dephosphorylation represents a potential regulatory mechanism for SRC-3 function, but the involved phosphatases were unknown.
  • Understanding SRC-3 regulation is vital for targeting its role in oncogenesis.

Purpose of the Study:

  • To identify human Ser/Thr phosphatases that negatively regulate SRC-3 transcriptional coregulatory activity.
  • To elucidate the specific roles of identified phosphatases in SRC-3 regulation and function.
  • To investigate the impact of SRC-3 dephosphorylation on its protein stability and oncogenic functions.

Main Methods:

  • Functional genomic screening of human Ser/Thr phosphatases targeting known SRC-3 phosphorylation sites.
  • Biochemical assays to assess dephosphorylation of SRC-3 by identified phosphatases.
  • Analysis of SRC-3 protein turnover and its association with estrogen receptor.
  • Investigation of SRC-3's role in breast cancer cell proliferation and invasion.

Main Results:

  • PDXP, PP1, and PP2A were identified as key negative regulators of SRC-3 transcriptional activity.
  • PDXP and PP2A dephosphorylate SRC-3, inhibiting its ligand-dependent association with the estrogen receptor.
  • PP1 dephosphorylates previously unknown sites (Ser101 and S102) within a degron, stabilizing SRC-3 protein and blocking proteasomal turnover.
  • PP1's regulation of SRC-3 impacts its oncogenic functions in breast cancer cells, including proliferation and invasion.

Conclusions:

  • PDXP, PP1, and PP2A are critical phosphatases that dephosphorylate and negatively regulate SRC-3.
  • PP1 plays a dual role by stabilizing SRC-3 protein and regulating its oncogenic activities.
  • These findings reveal novel regulatory mechanisms for SRC-3 and offer potential therapeutic targets in SRC-3-driven cancers.

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