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Akt finds its new path to regulate cell cycle through modulating Skp2 activity and its destruction by APC/Cdh1

Daming Gao1, Hiroyuki Inuzuka, Alan Tseng

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. wwei2@bidmc.harvard.edu.

Cell Division
|June 25, 2009
PubMed

Insights

Elevated Akt1 activity stabilizes Skp2 protein by preventing its degradation, promoting cancer cell growth. Targeting Akt1 may offer a new anti-cancer therapy by inhibiting Skp2 accumulation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Proteolysis

Background:

  • Skp2 overexpression is common in human cancers, but its regulation is not fully understood.
  • The anaphase-promoting complex/cyclosome (APC/Cdh1) complex targets proteins, including Skp2, for degradation.
  • The PI3K/Akt signaling pathway is frequently dysregulated in cancer.

Purpose of the Study:

  • To investigate the mechanisms controlling Skp2 stability in cancer.
  • To determine the role of Akt isoforms in Skp2 regulation.
  • To explore the link between Akt activity, Skp2 localization, and cancer progression.

Main Methods:

  • Western blotting to assess protein levels and phosphorylation.
  • Immunoprecipitation to study protein-protein interactions.
  • Immunofluorescence microscopy to determine protein localization.

Main Results:

  • Akt1, but not Akt2, directly inhibits Skp2 degradation by interfering with APC/Cdh1.
  • Elevated Akt activity protects Skp2 from degradation, leading to its accumulation.
  • Phosphorylation of Ser72 by Akt1 disrupts Skp2's Nuclear Localization Sequence (NLS), causing cytoplasmic translocation.
  • Cytoplasmic Skp2 correlates with aggressive breast and prostate cancers.

Conclusions:

  • Akt1 is a key regulator of Skp2 stability and localization.
  • The PI3K/Akt pathway influences APC/Cdh1-mediated proteolysis.
  • Akt1 inhibition represents a potential therapeutic strategy for cancers with elevated Skp2.

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