Abstract
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 (PIP3-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.
Highlights
IntroductionPTEN is a major tumor suppressor that antagonizes the PI3K/Akt ( known as protein kinase B, PKB) pro-survival and -proliferation signaling pathway by dephosphorylating the PLOS ONE | DOI:10.1371/journal.pone.0154771
PTEN is a major tumor suppressor that antagonizes the PI3K/Akt pro-survival and -proliferation signaling pathway by dephosphorylating the PLOS ONE | DOI:10.1371/journal.pone.0154771 May 3, 2016Fine-Tuning Pten Function Is Essential for Angiogenesis lipid second messenger phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2) [1]
PTEN subcellular localization is regulated by protein conformation, which in turn is largely dependent on the phosphorylation status of the PTEN C-terminal tail, regulating PTEN membrane and nuclear localization [23]
Summary
PTEN is a major tumor suppressor that antagonizes the PI3K/Akt ( known as protein kinase B, PKB) pro-survival and -proliferation signaling pathway by dephosphorylating the PLOS ONE | DOI:10.1371/journal.pone.0154771. Fine-Tuning Pten Function Is Essential for Angiogenesis lipid second messenger phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2) [1]. Upon loss of PTEN function, enhanced PIP3 signaling potentially drives cells into excessive proliferation and tumorigenesis by enhanced activation of the downstream effector, Akt [2,3]. Dephosphorylation of PIP3 is an event that occurs upon binding of PTEN to phospholipid-rich areas at the inner cell membrane [1,4]. There are other functions of PTEN, such as the regulation of DNA damage repair, genome stability, apoptosis, cell cycle progression or autophagy, that have been attributed to its nuclear localization [5,6,7,8,9,10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
