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Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB

Hui-Kuan Lin1, Guocan Wang, Zhenbang Chen

  • 1Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. hklin@mdanderson.org

Nature Cell Biology
|March 10, 2009
PubMed

Insights

Akt (also known as protein kinase B or PKB) directly phosphorylates Skp2, activating its E3 ligase activity. This Akt-dependent pathway promotes cell proliferation, migration, and tumorigenesis, offering a novel target for cancer therapy.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Skp2, an F-box protein, forms the SCF E3 ligase complex essential for ubiquitylation.
  • Skp2-mediated p27 degradation regulates cell cycle entry.
  • Skp2 overexpression and cytosolic accumulation are linked to tumorigenesis, but the latter's role is unclear.

Purpose of the Study:

  • To investigate the interaction between Akt/PKB and Skp2.
  • To elucidate the functional significance of Skp2 phosphorylation by Akt.
  • To determine the role of cytosolic Skp2 in cancer progression.

Main Methods:

  • Protein interaction studies
  • In vitro kinase assays
  • Site-directed mutagenesis
  • Cell proliferation and migration assays
  • Analysis of human cancer specimens

Main Results:

  • Akt/PKB directly phosphorylates Skp2.
  • Phosphorylation by Akt enhances SCF complex formation and E3 ligase activity.
  • A phosphorylation-defective Skp2 mutant shows impaired tumorigenesis and proliferation.
  • Akt-mediated phosphorylation induces 14-3-3beta-dependent Skp2 cytosolic relocalization.
  • Cytosolic Skp2 promotes cell migration.
  • Activated Akt correlates with cytosolic Skp2 accumulation in human cancers.

Conclusions:

  • Akt/PKB directly phosphorylates and activates Skp2's E3 ligase activity.
  • This novel Akt/PKB-Skp2 signaling pathway is proto-oncogenic, driving cell proliferation, migration, and tumorigenesis.
  • Cytosolic Skp2 plays a key role in regulating cell migration, and its accumulation is linked to cancer progression.

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