Phosphorylation of Akt and ERK1/2 Is Required for VEGF-A/VEGFR2-Induced Proliferation and Migration of Lymphatic Endothelium
Identifieur interne : 004522 ( Pmc/Curation ); précédent : 004521; suivant : 004523Phosphorylation of Akt and ERK1/2 Is Required for VEGF-A/VEGFR2-Induced Proliferation and Migration of Lymphatic Endothelium
Auteurs : Michael T. Dellinger [États-Unis] ; Rolf A. Brekken [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
There is growing evidence that vascular endothelial growth factor-A (VEGF-A), a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A/VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors.
Url:
DOI: 10.1371/journal.pone.0028947
PubMed: 22174934
PubMed Central: 3236226
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PMC:3236226Le document en format XML
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<author><name sortKey="Dellinger, Michael T" sort="Dellinger, Michael T" uniqKey="Dellinger M" first="Michael T." last="Dellinger">Michael T. Dellinger</name>
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<author><name sortKey="Brekken, Rolf A" sort="Brekken, Rolf A" uniqKey="Brekken R" first="Rolf A." last="Brekken">Rolf A. Brekken</name>
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<front><div type="abstract" xml:lang="en"><p>There is growing evidence that vascular endothelial growth factor-A (VEGF-A), a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A/VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors. <italic>In vitro</italic>
experiments with primary human dermal lymphatic endothelial cells (LECs) demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs. We show that VEGF-A stimulation of LECs leads to the phosphorylation of VEGFR2 (Tyr 951, 1054, 1059, 1175, and 1214) which subsequently triggers PKC dependent phosphorylation of ERK1/2 and PI3-K dependent phosphorylation of Akt. Additionally, we demonstrate that inhibitors that suppress the phosphorylation of ERK1/2 and Akt significantly block VEGF-A- induced proliferation and migration of LECs. Together, these results shed light on the mechanisms regulating VEGF-A-induced proliferation and migration of LECs, reveal that VEGFR2 is the primary signaling VEGF-A receptor on lymphatic endothelium, and suggest that therapeutic agents targeting the VEGF-A/VEGFR2 axis could be useful in blocking the pathological formation of lymphatic vessels.</p>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plosone</journal-id>
<journal-title-group><journal-title>PLoS ONE</journal-title>
</journal-title-group>
<issn pub-type="epub">1932-6203</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">22174934</article-id>
<article-id pub-id-type="pmc">3236226</article-id>
<article-id pub-id-type="publisher-id">PONE-D-11-12496</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0028947</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology</subject>
<subj-group><subject>Anatomy and Physiology</subject>
<subj-group><subject>Immune Physiology</subject>
<subj-group><subject>Lymphatic System</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Protein Interactions</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Developmental Biology</subject>
</subj-group>
<subj-group><subject>Molecular Cell Biology</subject>
<subj-group><subject>Signal Transduction</subject>
<subj-group><subject>Signaling Pathways</subject>
<subj-group><subject>Phosphoinositide Signal Transduction</subject>
</subj-group>
</subj-group>
<subj-group><subject>Signaling in Selected Disciplines</subject>
</subj-group>
</subj-group>
<subj-group><subject>Cell Division</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject>
<subj-group><subject>Cardiovascular</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Phosphorylation of Akt and ERK1/2 Is Required for VEGF-A/VEGFR2-Induced Proliferation and Migration of Lymphatic Endothelium</article-title>
<alt-title alt-title-type="running-head">VEGF-A/VEGFR2-Induced Lymphangiogenesis</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Dellinger</surname>
<given-names>Michael T.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brekken</surname>
<given-names>Rolf A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Kume</surname>
<given-names>Tsutomu</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">Feinberg Cardiovascular Research Institute, Northwestern University, United States of America</aff>
<author-notes><corresp id="cor1">* E-mail: <email>rolf.brekken@utsouthwestern.edu</email>
</corresp>
<fn fn-type="con"><p>Conceived and designed the experiments: MTD RAB. Performed the experiments: MTD. Analyzed the data: MTD RAB. Wrote the paper: MTD RAB.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2011</year>
</pub-date>
<pub-date pub-type="epub"><day>12</day>
<month>12</month>
<year>2011</year>
</pub-date>
<volume>6</volume>
<issue>12</issue>
<elocation-id>e28947</elocation-id>
<history><date date-type="received"><day>1</day>
<month>7</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>17</day>
<month>11</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>Dellinger, Brekken. 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 credited.</copyright-statement>
<copyright-year>2011</copyright-year>
</permissions>
<abstract><p>There is growing evidence that vascular endothelial growth factor-A (VEGF-A), a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A/VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors. <italic>In vitro</italic>
experiments with primary human dermal lymphatic endothelial cells (LECs) demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs. We show that VEGF-A stimulation of LECs leads to the phosphorylation of VEGFR2 (Tyr 951, 1054, 1059, 1175, and 1214) which subsequently triggers PKC dependent phosphorylation of ERK1/2 and PI3-K dependent phosphorylation of Akt. Additionally, we demonstrate that inhibitors that suppress the phosphorylation of ERK1/2 and Akt significantly block VEGF-A- induced proliferation and migration of LECs. Together, these results shed light on the mechanisms regulating VEGF-A-induced proliferation and migration of LECs, reveal that VEGFR2 is the primary signaling VEGF-A receptor on lymphatic endothelium, and suggest that therapeutic agents targeting the VEGF-A/VEGFR2 axis could be useful in blocking the pathological formation of lymphatic vessels.</p>
</abstract>
<counts><page-count count="9"></page-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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