Cell 2011,
PMID: 21241890
Song, Min Sup; Carracedo, Arkaitz; Salmena, Leonardo; Song, Su Jung; Egia, Ainara; Malumbres, Marcos; Pandolfi, Pier Paolo
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:
Diseases/Pathways annotated by Medline MESH: Prostatic Neoplasms
Document information provided by NCBI PubMed
Text Mining Data
APC-CDH1 → PTEN: "
Nuclear
PTEN regulates the
APC-CDH1 tumor-suppressive complex in a phosphatase independent manner
"
APC-CDH1 → PTEN: "
Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase independent manner
"
CDH1 → PTEN: "
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
"
APC-CDH1 → PTEN: "
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
"
APC-CDH1 ⊣ PTEN: "
We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1
"
APC-CDH1 ⊣ PTEN: "
We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1
"
Manually curated Databases
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IRef Biogrid Interaction:
CDC27
—
ANAPC5
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ANAPC4
—
CDC27
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
FZR1
—
CCNB1
(direct interaction, enzymatic study)
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IRef Biogrid Interaction:
ANAPC7
—
CDC27
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
HIST1H1A
—
CCNE1
(direct interaction, enzymatic study)
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IRef Biogrid Interaction:
CCNA2
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HIST1H1A
(direct interaction, enzymatic study)
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IRef Biogrid Interaction:
PTEN
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ANAPC4
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
UBC
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ETS2
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PTEN
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ANAPC5
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PTEN
—
FZR1
(direct interaction, pull down)
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IRef Biogrid Interaction:
PTEN
—
FZR1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PTEN
—
ANAPC7
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
HIST1H1A
—
CDK2
(direct interaction, enzymatic study)
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IRef Biogrid Interaction:
FZR1
—
CDC27
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PTEN
—
CDC27
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PTEN
—
CDC27
(direct interaction, pull down)
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IRef Biogrid Interaction:
CCNB1
—
UBC
(physical association, affinity chromatography technology)
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IRef Intact Interaction:
FZR1
—
CDC27
(physical association, anti bait coimmunoprecipitation)
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IRef Intact Interaction:
PTEN
—
CDC27
(colocalization, fluorescence microscopy)
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IRef Intact Interaction:
PTEN
—
CDC27
(physical association, anti tag coimmunoprecipitation)
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IRef Intact Interaction:
PTEN
—
CDC27
(physical association, fluorescence microscopy)
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IRef Intact Interaction:
Complex of 16 proteins
(association, anti bait coimmunoprecipitation)
In total, 18 gene pairs are associated to this article in curated databases