[HTML][HTML] Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner

MS Song, A Carracedo, L Salmena, SJ Song, A Egia… - Cell, 2011 - cell.com
MS Song, A Carracedo, L Salmena, SJ Song, A Egia, M Malumbres, PP Pandolfi
Cell, 2011cell.com
PTEN 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 …
Summary
PTEN 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
cell.com