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The PTEN Tumor Suppressor Forms Homodimers in Solution.


ABSTRACT: As the phosphoinositol-3-kinase antagonist in the PI3K pathway, the PTEN tumor suppressor exerts phosphatase activity on diacylphosphatidylinositol triphosphate in the plasma membrane. Even partial loss of this activity enhances tumorigenesis, but a mechanistic basis for this aspect of PTEN physiology has not yet been established. It was recently proposed that PTEN mutations have dominant-negative effects in cancer via PTEN dimers. We show that PTEN forms homodimers in vitro, and determine a structural model of the complex from SAXS and Rosetta docking studies. Our findings shed new light on the cellular control mechanism of PTEN activity. Phosphorylation of the unstructured C-terminal tail of PTEN reduces PTEN activity, and this result was interpreted as a blockage of the PTEN membrane binding interface through this tail. The results presented here instead suggest that the C-terminal tail functions in stabilizing the homodimer, and that tail phosphorylation interferes with this stabilization.

SUBMITTER: Heinrich F 

PROVIDER: S-EPMC4598300 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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The PTEN Tumor Suppressor Forms Homodimers in Solution.

Heinrich Frank F   Chakravarthy Srinivas S   Nanda Hirsh H   Papa Antonella A   Pandolfi Pier Paolo PP   Ross Alonzo H AH   Harishchandra Rakesh K RK   Gericke Arne A   Lösche Mathias M  

Structure (London, England : 1993) 20150820 10


As the phosphoinositol-3-kinase antagonist in the PI3K pathway, the PTEN tumor suppressor exerts phosphatase activity on diacylphosphatidylinositol triphosphate in the plasma membrane. Even partial loss of this activity enhances tumorigenesis, but a mechanistic basis for this aspect of PTEN physiology has not yet been established. It was recently proposed that PTEN mutations have dominant-negative effects in cancer via PTEN dimers. We show that PTEN forms homodimers in vitro, and determine a str  ...[more]

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