Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction.
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.
Gao
Daming
D
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Inuzuka
Hiroyuki
H
Tseng
Alan
A
Chin
Rebecca Y
RY
Toker
Alex
A
Wei
Wenyi
W
D000595:Amino Acid Sequence; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D047389:Casein Kinase I / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D044786:S-Phase Kinase-Associated Proteins; D010768:Phosphoserine; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D019869:Phosphatidylinositol 3-Kinases; D047389:Casein Kinase I; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human