Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
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:
Mesh Terms:
Animals, Cadherins, Cell Aging, Cell Line, Tumor, Cell Nucleus, Humans, Male, Mice, Neoplasm Transplantation, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases, Prostatic Neoplasms, Protein-Serine-Threonine Kinases, Transplantation, Heterologous, Ubiquitin-Protein Ligase Complexes
Animals, Cadherins, Cell Aging, Cell Line, Tumor, Cell Nucleus, Humans, Male, Mice, Neoplasm Transplantation, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases, Prostatic Neoplasms, Protein-Serine-Threonine Kinases, Transplantation, Heterologous, Ubiquitin-Protein Ligase Complexes
Cell
Date: Jan. 21, 2011
PubMed ID: 21241890
View in: Pubmed Google Scholar
Download Curated Data For This Publication
151286
Switch View:
- Interactions 21
- PTM Genes 2