| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2036174 | Cell | 2011 | 13 Pages |
SummaryPTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (4923 K)
Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (189 K)Download as PowerPoint slideHighlights► PTEN binds and promotes APC-CDH1 complex activation in the nucleus ► Proliferation and senescence are affected by reduction of APC activity upon PTEN loss ► The phosphatase activity of PTEN is dispensable for the regulation of APC ► PTEN null and catalytic mutants are differentially sensitive to inhibitors of APC targets
