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Phosphorylation of the anaphase-promoting complex/Cdc27 is involved in TGF-beta signaling

Liyong Zhang1, Takeo Fujita, George Wu

  • 1Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.

The Journal of Biological Chemistry
|January 7, 2011
PubMed

Insights

Transforming growth factor-beta (TGF-β) signaling loss in tumors is linked to cancer. This study reveals casein kinase II (CKII) phosphorylates Cdc27, activating the anaphase-promoting complex (APC) for cell cycle arrest.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Loss of TGF-β-induced growth inhibition is a hallmark of human tumors.
  • The anaphase-promoting complex (APC/cyclosome) is implicated in TGF-β signaling, promoting SnoN degradation and cell cycle arrest.
  • The precise mechanism of APC activation by TGF-β remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of APC activation in response to TGF-β signaling.
  • To investigate the role of Cdc27 phosphorylation in TGF-β-induced APC activation.
  • To identify the kinase responsible for Cdc27 phosphorylation in this pathway.

Main Methods:

  • Investigated TGF-β signaling effects on Cdc27 phosphorylation.
  • Utilized shRNA to deplete casein kinase II (CKII).
  • Employed site-directed mutagenesis of Cdc27 (S154A) and phosphorylation-resistant mutants.

Main Results:

  • TGF-β signaling induces Cdc27 phosphorylation, facilitating APC activation.
  • CKII is identified as the kinase responsible for Cdc27 phosphorylation in response to TGF-β.
  • CKII depletion abrogates TGF-β-induced Cdc27 phosphorylation and SnoN degradation.
  • Cdc27 mutations impair TGF-β-induced SnoN degradation and growth inhibition.

Conclusions:

  • Phosphorylation of Cdc27 by CKII is a key step in TGF-β-induced APC activation.
  • This pathway is crucial for TGF-β-mediated growth inhibition and tumor suppression.

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