Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels

Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels

Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological funct...

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Main Authors: Verma, Kiran, Gu, Jingsheng, Werner, Erica
Format: Online
Language:English
Published: Public Library of Science 2011
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148219/
id pubmed-3148219
recordtype oai_dc
spelling pubmed-31482192011-08-09 Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels Verma, Kiran Gu, Jingsheng Werner, Erica Research Article Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological function in blood vessels remains largely unknown. We identified the chicken chorioallantoic membrane (CAM) as a model system to study the endogenous function of TEM8 in blood vessels as we found that TEM8 expression was induced transiently between day 10 and 12 of embryonic development, when the vascular tree is undergoing final development and growth. We used the cell-binding component of anthrax toxin, Protective Antigen (PA), to engage endogenous TEM8 receptors and evaluate the effects of PA-TEM8 complexes on vascular development. PA applied at the time of highest TEM8 expression reduced vascular density and disrupted hierarchical branching as revealed by quantitative morphometric analysis of the vascular tree after 48h. PA-dependent reduced branching phenotype was partially mimicked by Wnt3a application and ameliorated by the Wnt antagonist, Dikkopf-1. These results implicate TEM8 expression in endothelial cells in regulating the canonical Wnt signaling pathway at this day of CAM development. Consistent with this model, PA increased beta catenin levels acutely in CAM blood vessels in vivo and in TEM8 transfected primary human endothelial cells in vitro. TEM8 expression in Hek293 cells, which neither express endogenous PA-binding receptors nor Wnt ligands, stabilized beta catenin levels and amplified beta catenin-dependent transcriptional activity induced by Wnt3a. This agonistic function is supported by findings in the CAM, where the increase in TEM8 expression from day 10 to day 12 and PA application correlated with Axin 2 induction, a universal reporter gene for canonical Wnt signaling. We postulate that the developmentally controlled expression of TEM8 modulates endothelial cell response to canonical Wnt signaling to regulate vessel patterning and density. Public Library of Science 2011-08-01 /pmc/articles/PMC3148219/ /pubmed/21829615 http://dx.doi.org/10.1371/journal.pone.0022334 Text en Verma 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Verma, Kiran
Gu, Jingsheng
Werner, Erica
spellingShingle Verma, Kiran
Gu, Jingsheng
Werner, Erica
Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels
author_facet Verma, Kiran
Gu, Jingsheng
Werner, Erica
author_sort Verma, Kiran
title Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels
title_short Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels
title_full Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels
title_fullStr Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels
title_full_unstemmed Tumor Endothelial Marker 8 Amplifies Canonical Wnt Signaling in Blood Vessels
title_sort tumor endothelial marker 8 amplifies canonical wnt signaling in blood vessels
description Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological function in blood vessels remains largely unknown. We identified the chicken chorioallantoic membrane (CAM) as a model system to study the endogenous function of TEM8 in blood vessels as we found that TEM8 expression was induced transiently between day 10 and 12 of embryonic development, when the vascular tree is undergoing final development and growth. We used the cell-binding component of anthrax toxin, Protective Antigen (PA), to engage endogenous TEM8 receptors and evaluate the effects of PA-TEM8 complexes on vascular development. PA applied at the time of highest TEM8 expression reduced vascular density and disrupted hierarchical branching as revealed by quantitative morphometric analysis of the vascular tree after 48h. PA-dependent reduced branching phenotype was partially mimicked by Wnt3a application and ameliorated by the Wnt antagonist, Dikkopf-1. These results implicate TEM8 expression in endothelial cells in regulating the canonical Wnt signaling pathway at this day of CAM development. Consistent with this model, PA increased beta catenin levels acutely in CAM blood vessels in vivo and in TEM8 transfected primary human endothelial cells in vitro. TEM8 expression in Hek293 cells, which neither express endogenous PA-binding receptors nor Wnt ligands, stabilized beta catenin levels and amplified beta catenin-dependent transcriptional activity induced by Wnt3a. This agonistic function is supported by findings in the CAM, where the increase in TEM8 expression from day 10 to day 12 and PA application correlated with Axin 2 induction, a universal reporter gene for canonical Wnt signaling. We postulate that the developmentally controlled expression of TEM8 modulates endothelial cell response to canonical Wnt signaling to regulate vessel patterning and density.
publisher Public Library of Science
publishDate 2011
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148219/
_version_ 1611468647899856896

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