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Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis

The lipid- and protein phosphatase PTEN is an essential tumor suppressor that is highly conserved among all higher eukaryotes. As an antagonist of the PI3K/Akt cell survival and proliferation pathway, it exerts its most prominent function at the cell membrane, but (PIP(3)-independent) functions of n...

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Autores principales: Stumpf, Miriam, Blokzijl-Franke, Sasja, den Hertog, Jeroen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854392/
https://www.ncbi.nlm.nih.gov/pubmed/27138341
http://dx.doi.org/10.1371/journal.pone.0154771
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author Stumpf, Miriam
Blokzijl-Franke, Sasja
den Hertog, Jeroen
author_facet Stumpf, Miriam
Blokzijl-Franke, Sasja
den Hertog, Jeroen
author_sort Stumpf, Miriam
collection PubMed
description The lipid- and protein phosphatase PTEN is an essential tumor suppressor that is highly conserved among all higher eukaryotes. As an antagonist of the PI3K/Akt cell survival and proliferation pathway, it exerts its most prominent function at the cell membrane, but (PIP(3)-independent) functions of nuclear PTEN have been discovered as well. PTEN subcellular localization is tightly controlled by its protein conformation. In the closed conformation, PTEN localizes predominantly to the cytoplasm. Opening up of the conformation of PTEN exposes N-terminal and C-terminal regions of the protein that are required for both interaction with the cell membrane and translocation to the nucleus. Lack of Pten leads to hyperbranching of the intersegmental vessels during zebrafish embryogenesis, which is rescued by expression of exogenous Pten. Here, we observed that expression of mutant PTEN with an open conformation rescued the hyperbranching phenotype in pten double homozygous embryos and suppressed the increased p-Akt levels that are characteristic for embryos lacking Pten. In addition, in pten mutant and wild type embryos alike, open conformation PTEN induced stalled intersegmental vessels, which fail to connect with the dorsal longitudinal anastomotic vessel. Functional hyperactivity of open conformation PTEN in comparison to wild type PTEN seems to result predominantly from its enhanced recruitment to the cell membrane. Enhanced recruitment of phosphatase inactive mutants to the membrane did not induce the stalled vessel phenotype nor did it rescue the hyperbranching phenotype in pten double homozygous embryos, indicating that PTEN phosphatase activity is indispensable for its regulatory function during angiogenesis. Taken together, our data suggest that PTEN phosphatase activity needs to be carefully fine-tuned for normal embryogenesis and that the control of its subcellular localization is a key mechanism in this process.
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spelling pubmed-48543922016-05-07 Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis Stumpf, Miriam Blokzijl-Franke, Sasja den Hertog, Jeroen PLoS One Research Article The lipid- and protein phosphatase PTEN is an essential tumor suppressor that is highly conserved among all higher eukaryotes. As an antagonist of the PI3K/Akt cell survival and proliferation pathway, it exerts its most prominent function at the cell membrane, but (PIP(3)-independent) functions of nuclear PTEN have been discovered as well. PTEN subcellular localization is tightly controlled by its protein conformation. In the closed conformation, PTEN localizes predominantly to the cytoplasm. Opening up of the conformation of PTEN exposes N-terminal and C-terminal regions of the protein that are required for both interaction with the cell membrane and translocation to the nucleus. Lack of Pten leads to hyperbranching of the intersegmental vessels during zebrafish embryogenesis, which is rescued by expression of exogenous Pten. Here, we observed that expression of mutant PTEN with an open conformation rescued the hyperbranching phenotype in pten double homozygous embryos and suppressed the increased p-Akt levels that are characteristic for embryos lacking Pten. In addition, in pten mutant and wild type embryos alike, open conformation PTEN induced stalled intersegmental vessels, which fail to connect with the dorsal longitudinal anastomotic vessel. Functional hyperactivity of open conformation PTEN in comparison to wild type PTEN seems to result predominantly from its enhanced recruitment to the cell membrane. Enhanced recruitment of phosphatase inactive mutants to the membrane did not induce the stalled vessel phenotype nor did it rescue the hyperbranching phenotype in pten double homozygous embryos, indicating that PTEN phosphatase activity is indispensable for its regulatory function during angiogenesis. Taken together, our data suggest that PTEN phosphatase activity needs to be carefully fine-tuned for normal embryogenesis and that the control of its subcellular localization is a key mechanism in this process. Public Library of Science 2016-05-03 /pmc/articles/PMC4854392/ /pubmed/27138341 http://dx.doi.org/10.1371/journal.pone.0154771 Text en © 2016 Stumpf et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Stumpf, Miriam
Blokzijl-Franke, Sasja
den Hertog, Jeroen
Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis
title Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis
title_full Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis
title_fullStr Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis
title_full_unstemmed Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis
title_short Fine-Tuning of Pten Localization and Phosphatase Activity Is Essential for Zebrafish Angiogenesis
title_sort fine-tuning of pten localization and phosphatase activity is essential for zebrafish angiogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854392/
https://www.ncbi.nlm.nih.gov/pubmed/27138341
http://dx.doi.org/10.1371/journal.pone.0154771
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