Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction

Daming Gao, Hiroyuki Inuzuka, Alan Tseng, Rebecca Y. Chin, Alex Toker, Wenyi Wei

Research output: Contribution to journalArticlepeer-review

180 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)397-408
Number of pages12
JournalNature cell biology
Volume11
Issue number4
DOIs
Publication statusPublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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