Vascular Endothelial Growth Factor Receptor-3 Directly Interacts with Phosphatidylinositol 3-Kinase to Regulate Lymphangiogenesis
Identifieur interne : 003D50 ( Main/Exploration ); précédent : 003D49; suivant : 003D51Vascular Endothelial Growth Factor Receptor-3 Directly Interacts with Phosphatidylinositol 3-Kinase to Regulate Lymphangiogenesis
Auteurs : Sanja Coso [Australie] ; Yiping Zeng [Australie] ; Kenneth Opeskin [Australie] ; Elizabeth D. Williams [Australie]Source :
- PLoS ONE [ 1932-6203 ] ; 2012.
Descripteurs français
- KwdFr :
- Cellules cultivées, Cellules endothéliales (métabolisme), Humains, Immunoprécipitation, Lymphangiogenèse (génétique), Lymphangiogenèse (physiologie), Mitogen-Activated Protein Kinase 1 (métabolisme), Mitogen-Activated Protein Kinase 3 (métabolisme), Nitric oxide synthase type III (métabolisme), Phosphatidylinositol 3-kinase (métabolisme), Phosphorylation, Protéines proto-oncogènes c-akt (métabolisme), Ribosomal Protein S6 Kinases, 70-kDa (métabolisme), Récepteur-3 au facteur croissance endothéliale vasculaire (métabolisme), Technique de Western, Techniques in vitro.
- MESH :
- génétique : Lymphangiogenèse.
- métabolisme : Cellules endothéliales, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Nitric oxide synthase type III, Phosphatidylinositol 3-kinase, Protéines proto-oncogènes c-akt, Ribosomal Protein S6 Kinases, 70-kDa, Récepteur-3 au facteur croissance endothéliale vasculaire.
- physiologie : Lymphangiogenèse.
- Cellules cultivées, Humains, Immunoprécipitation, Phosphorylation, Technique de Western, Techniques in vitro.
English descriptors
- KwdEn :
- Blotting, Western, Cells, Cultured, Endothelial Cells (metabolism), Humans, Immunoprecipitation, In Vitro Techniques, Lymphangiogenesis (genetics), Lymphangiogenesis (physiology), Mitogen-Activated Protein Kinase 1 (metabolism), Mitogen-Activated Protein Kinase 3 (metabolism), Nitric Oxide Synthase Type III (metabolism), Phosphatidylinositol 3-Kinase (metabolism), Phosphorylation, Proto-Oncogene Proteins c-akt (metabolism), Ribosomal Protein S6 Kinases, 70-kDa (metabolism), Vascular Endothelial Growth Factor Receptor-3 (metabolism).
- MESH :
- chemical , metabolism : Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Nitric Oxide Synthase Type III, Phosphatidylinositol 3-Kinase, Proto-Oncogene Proteins c-akt, Ribosomal Protein S6 Kinases, 70-kDa, Vascular Endothelial Growth Factor Receptor-3.
- genetics : Lymphangiogenesis.
- metabolism : Endothelial Cells.
- physiology : Lymphangiogenesis.
- Blotting, Western, Cells, Cultured, Humans, Immunoprecipitation, In Vitro Techniques, Phosphorylation.
Abstract
Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood.
Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both
Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.
Url:
DOI: 10.1371/journal.pone.0039558
PubMed: 22745786
PubMed Central: 3382126
Affiliations:
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Le document en format XML
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Williams</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Blotting, Western</term><term>Cells, Cultured</term><term>Endothelial Cells (metabolism)</term><term>Humans</term><term>Immunoprecipitation</term><term>In Vitro Techniques</term><term>Lymphangiogenesis (genetics)</term><term>Lymphangiogenesis (physiology)</term><term>Mitogen-Activated Protein Kinase 1 (metabolism)</term><term>Mitogen-Activated Protein Kinase 3 (metabolism)</term><term>Nitric Oxide Synthase Type III (metabolism)</term><term>Phosphatidylinositol 3-Kinase (metabolism)</term><term>Phosphorylation</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Ribosomal Protein S6 Kinases, 70-kDa (metabolism)</term><term>Vascular Endothelial Growth Factor Receptor-3 (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cellules cultivées</term><term>Cellules endothéliales (métabolisme)</term><term>Humains</term><term>Immunoprécipitation</term><term>Lymphangiogenèse (génétique)</term><term>Lymphangiogenèse (physiologie)</term><term>Mitogen-Activated Protein Kinase 1 (métabolisme)</term><term>Mitogen-Activated Protein Kinase 3 (métabolisme)</term><term>Nitric oxide synthase type III (métabolisme)</term><term>Phosphatidylinositol 3-kinase (métabolisme)</term><term>Phosphorylation</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Ribosomal Protein S6 Kinases, 70-kDa (métabolisme)</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire (métabolisme)</term><term>Technique de Western</term><term>Techniques in vitro</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mitogen-Activated Protein Kinase 1</term><term>Mitogen-Activated Protein Kinase 3</term><term>Nitric Oxide Synthase Type III</term><term>Phosphatidylinositol 3-Kinase</term><term>Proto-Oncogene Proteins c-akt</term><term>Ribosomal Protein S6 Kinases, 70-kDa</term><term>Vascular Endothelial Growth Factor Receptor-3</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lymphangiogenesis</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Lymphangiogenèse</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Endothelial Cells</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules endothéliales</term><term>Mitogen-Activated Protein Kinase 1</term><term>Mitogen-Activated Protein Kinase 3</term><term>Nitric oxide synthase type III</term><term>Phosphatidylinositol 3-kinase</term><term>Protéines proto-oncogènes c-akt</term><term>Ribosomal Protein S6 Kinases, 70-kDa</term><term>Récepteur-3 au facteur croissance endothéliale vasculaire</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Lymphangiogenèse</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Lymphangiogenesis</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Blotting, Western</term><term>Cells, Cultured</term><term>Humans</term><term>Immunoprecipitation</term><term>In Vitro Techniques</term><term>Phosphorylation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cellules cultivées</term><term>Humains</term><term>Immunoprécipitation</term><term>Phosphorylation</term><term>Technique de Western</term><term>Techniques in vitro</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood.</p></sec><sec><title>Methods and Results</title><p>Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both <italic>in vitro</italic> and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration.</p></sec><sec><title>Conclusions</title><p>Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Osaki, T" uniqKey="Osaki T">T Osaki</name></author><author><name sortKey="Nagashima, A" uniqKey="Nagashima A">A Nagashima</name></author><author><name sortKey="Yoshimatsu, T" uniqKey="Yoshimatsu T">T Yoshimatsu</name></author><author><name sortKey="Tashima, Y" uniqKey="Tashima Y">Y Tashima</name></author><author><name sortKey="Yasumoto, K" uniqKey="Yasumoto K">K Yasumoto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morton, Dl" uniqKey="Morton D">DL Morton</name></author><author><name sortKey="Thompson, Jf" uniqKey="Thompson J">JF Thompson</name></author><author><name sortKey="Cochran, Aj" uniqKey="Cochran A">AJ Cochran</name></author><author><name sortKey="Mozzillo, N" uniqKey="Mozzillo 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Opeskin</name><name sortKey="Williams, Elizabeth D" sort="Williams, Elizabeth D" uniqKey="Williams E" first="Elizabeth D." last="Williams">Elizabeth D. 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