Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction
- 8 March 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 11 (4), 397-408
- https://doi.org/10.1038/ncb1847
Abstract
Skp2 is a known component of the SCF ubiquitin ligase that targets the cell-cycle regulator p27. Akt kinase phosphorylates Skp2 and regulates its stability and cytoplasmic localization. Deregulated Skp2 function promotes cell transformation, and this is consistent with observations of Skp2 overexpression in many human cancers. However, the mechanisms underlying elevated Skp2 expression are still unknown. Here we show that the serine/threonine protein kinase Akt1, but not Akt2, directly controls Skp2 stability by a mechanism that involves degradation by the APC–Cdh1 ubiquitin ligase complex. We show further that Akt1 phosphorylates Skp2 at Ser 72, which is required to disrupt the interaction between Cdh1 and Skp2. In addition, we show that Ser 72 is localized within a putative nuclear localization sequence and that phosphorylation of Ser 72 by Akt leads to cytoplasmic translocation of Skp2. This finding expands our knowledge of how specific signalling kinase cascades influence proteolysis governed by APC–Cdh1 complexes, and provides evidence that elevated Akt activity and cytoplasmic Skp2 expression may be causative for cancer progression.Keywords
This publication has 49 references indexed in Scilit:
- Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APCCdh1 in G1 phaseThe EMBO Journal, 2008
- A cell cycle regulatory network controlling NF-κB subunit activity and functionThe EMBO Journal, 2007
- Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 BindingMolecular and Cellular Biology, 2006
- Akt Blocks Breast Cancer Cell Motility and Invasion through the Transcription Factor NFATMolecular Cell, 2005
- Regulation of Nuclear Transport: Central Role in Development and Transformation?Traffic, 2005
- Protein Phosphatase 2A Dephosphorylation of Phosphoserine 112 Plays the Gatekeeper Role for BAD-Mediated ApoptosisMolecular and Cellular Biology, 2003
- Phosphoprotein Analysis Using Antibodies Broadly Reactive against Phosphorylated MotifsJournal of Biological Chemistry, 2002
- Cell Density and Phosphorylation Control the Subcellular Localization of Adenomatous Polyposis Coli ProteinMolecular and Cellular Biology, 2001
- Akt Phosphorylation Site Found in Human Caspase-9 Is Absent in Mouse Caspase-9Biochemical and Biophysical Research Communications, 1999
- Phosphorylation on protein kinase C sites inhibits nuclear import of lamin B2.The Journal of cell biology, 1993