TY - JOUR
T1 - Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner
AU - Song, Min Sup
AU - Carracedo, Arkaitz
AU - Salmena, Leonardo
AU - Song, Su Jung
AU - Egia, Ainara
AU - Malumbres, Marcos
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We are grateful to former and present members of the Pandolfi lab for experimental support, advice, or discussion. We are thankful to Drs. Manuel Serrano, Pumin Zhang, Wenyi Wei, and Hongtao Yu for providing reagents. We thank Dr. John Asara for mass-spectrometric analysis. This work was supported by NIH grants to P.P.P. A.C. is supported by a Long-Term Fellowship Award from the European Molecular Biology Organization, and L.S. is supported by a Fellowship from the Canadian Institutes of Health Research.
PY - 2011/1/21
Y1 - 2011/1/21
N2 - 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:
AB - 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:
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U2 - 10.1016/j.cell.2010.12.020
DO - 10.1016/j.cell.2010.12.020
M3 - Article
C2 - 21241890
AN - SCOPUS:78651482046
SN - 0092-8674
VL - 144
SP - 187
EP - 199
JO - Cell
JF - Cell
IS - 2
ER -