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Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function
New blood vessel sprouting (angiogenesis) and vascular physiology are fundamental features of metazoan species but we do not fully understand how signal transduction pathways regulate diverse vascular responses. The vascular endothelial growth factor (VEGF) family bind membrane-bound receptor tyrosi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550078/ https://www.ncbi.nlm.nih.gov/pubmed/31072823 http://dx.doi.org/10.1242/bio.034215 |
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author | Fearnley, Gareth W. Abdul-Zani, Izma Latham, Antony M. Hollstein, Monica C. Ladbury, John E. Wheatcroft, Stephen B. Odell, Adam F. Ponnambalam, Sreenivasan |
author_facet | Fearnley, Gareth W. Abdul-Zani, Izma Latham, Antony M. Hollstein, Monica C. Ladbury, John E. Wheatcroft, Stephen B. Odell, Adam F. Ponnambalam, Sreenivasan |
author_sort | Fearnley, Gareth W. |
collection | PubMed |
description | New blood vessel sprouting (angiogenesis) and vascular physiology are fundamental features of metazoan species but we do not fully understand how signal transduction pathways regulate diverse vascular responses. The vascular endothelial growth factor (VEGF) family bind membrane-bound receptor tyrosine kinases (VEGFRs), which trigger multiple signal transduction pathways and diverse cellular responses. We evaluated whether the MAP3K family member and proto-oncoprotein Tpl2 (MAP3K8) regulates basal and VEGF-A-stimulated signal transduction in endothelial cells. Notably, stimulation with exogenous VEGF-A increased Tpl2 mRNA levels and consequently de novo protein synthesis. Depletion of Tpl2 levels reveals a role in both basal and VEGF-A-stimulated endothelial cell responses, including endothelial-leukocyte interactions, monolayer permeability and new blood vessel formation. Under basal conditions, Tpl2 modulates a signal transduction cascade resulting in phosphorylation of a nuclear transcription factor (ATF-2) and altered endothelial gene expression, a pathway previously identified as crucial in VEGF-dependent vascular responses. Loss of Tpl2 expression or activity impairs signal transduction through Akt, eNOS and ATF-2, broadly impacting on endothelial function. Our study now provides a mechanism for Tpl2 as a central component of signal transduction pathways in the endothelium. |
format | Online Article Text |
id | pubmed-6550078 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-65500782019-06-07 Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function Fearnley, Gareth W. Abdul-Zani, Izma Latham, Antony M. Hollstein, Monica C. Ladbury, John E. Wheatcroft, Stephen B. Odell, Adam F. Ponnambalam, Sreenivasan Biol Open Research Article New blood vessel sprouting (angiogenesis) and vascular physiology are fundamental features of metazoan species but we do not fully understand how signal transduction pathways regulate diverse vascular responses. The vascular endothelial growth factor (VEGF) family bind membrane-bound receptor tyrosine kinases (VEGFRs), which trigger multiple signal transduction pathways and diverse cellular responses. We evaluated whether the MAP3K family member and proto-oncoprotein Tpl2 (MAP3K8) regulates basal and VEGF-A-stimulated signal transduction in endothelial cells. Notably, stimulation with exogenous VEGF-A increased Tpl2 mRNA levels and consequently de novo protein synthesis. Depletion of Tpl2 levels reveals a role in both basal and VEGF-A-stimulated endothelial cell responses, including endothelial-leukocyte interactions, monolayer permeability and new blood vessel formation. Under basal conditions, Tpl2 modulates a signal transduction cascade resulting in phosphorylation of a nuclear transcription factor (ATF-2) and altered endothelial gene expression, a pathway previously identified as crucial in VEGF-dependent vascular responses. Loss of Tpl2 expression or activity impairs signal transduction through Akt, eNOS and ATF-2, broadly impacting on endothelial function. Our study now provides a mechanism for Tpl2 as a central component of signal transduction pathways in the endothelium. The Company of Biologists Ltd 2019-05-09 /pmc/articles/PMC6550078/ /pubmed/31072823 http://dx.doi.org/10.1242/bio.034215 Text en © 2019. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Fearnley, Gareth W. Abdul-Zani, Izma Latham, Antony M. Hollstein, Monica C. Ladbury, John E. Wheatcroft, Stephen B. Odell, Adam F. Ponnambalam, Sreenivasan Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function |
title | Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function |
title_full | Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function |
title_fullStr | Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function |
title_full_unstemmed | Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function |
title_short | Tpl2 is required for VEGF-A-stimulated signal transduction and endothelial cell function |
title_sort | tpl2 is required for vegf-a-stimulated signal transduction and endothelial cell function |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550078/ https://www.ncbi.nlm.nih.gov/pubmed/31072823 http://dx.doi.org/10.1242/bio.034215 |
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