Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function
Identifieur interne : 000687 ( Pmc/Curation ); précédent : 000686; suivant : 000688Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function
Auteurs : Rachel J. Roth Flach ; Chang-An Guo ; Laura V. Danai ; Joseph C. Yawe ; Sharvari Gujja ; Yvonne J. K. Edwards ; Michael P. CzechSource :
- Molecular and Cellular Biology [ 0270-7306 ] ; 2016.
Abstract
The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.
Url:
DOI: 10.1128/MCB.01121-15
PubMed: 27044870
PubMed Central: 4907094
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<author><name sortKey="Roth Flach, Rachel J" sort="Roth Flach, Rachel J" uniqKey="Roth Flach R" first="Rachel J." last="Roth Flach">Rachel J. Roth Flach</name>
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<author><name sortKey="Guo, Chang An" sort="Guo, Chang An" uniqKey="Guo C" first="Chang-An" last="Guo">Chang-An Guo</name>
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<author><name sortKey="Danai, Laura V" sort="Danai, Laura V" uniqKey="Danai L" first="Laura V." last="Danai">Laura V. Danai</name>
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<author><name sortKey="Yawe, Joseph C" sort="Yawe, Joseph C" uniqKey="Yawe J" first="Joseph C." last="Yawe">Joseph C. Yawe</name>
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<front><div type="abstract" xml:lang="en"><p>The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Cell Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Mol. Cell. Biol</journal-id>
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<title-group><article-title>Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function</article-title>
<alt-title alt-title-type="running-head">Endothelial MAP4K4 in Lymphatic Vascular Development</alt-title>
<alt-title alt-title-type="short-authors">Roth Flach et al.</alt-title>
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<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Roth Flach</surname>
<given-names>Rachel J.</given-names>
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<xref ref-type="author-notes" rid="fn1">*</xref>
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<contrib contrib-type="author"><name><surname>Guo</surname>
<given-names>Chang-An</given-names>
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<xref ref-type="author-notes" rid="fn1">*</xref>
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<contrib contrib-type="author"><name><surname>Danai</surname>
<given-names>Laura V.</given-names>
</name>
<xref ref-type="author-notes" rid="fn1">*</xref>
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<contrib contrib-type="author"><name><surname>Yawe</surname>
<given-names>Joseph C.</given-names>
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<contrib contrib-type="author"><name><surname>Gujja</surname>
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<contrib contrib-type="author"><name><surname>Edwards</surname>
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<contrib contrib-type="author" corresp="yes"><name><surname>Czech</surname>
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<aff>Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA</aff>
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<author-notes><corresp id="cor1">Address correspondence to Rachel J. Roth Flach, <email>Rachel.Rothflach@pfizer.com</email>
, or Michael P. Czech, <email>Michael.Czech@umassmed.edu</email>
.</corresp>
<fn id="fn1" fn-type="present-address"><label>*</label>
<p>Present address: Rachel J. Roth Flach, Pfizer, Cambridge, Massachusetts, USA; Chang-An Guo, Department of Biochemistry, University of Wisconsin—Madison, Madison, Wisconsin, USA; Laura V. Danai, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.</p>
</fn>
<fn fn-type="other"><p><bold>Citation</bold>
Roth Flach RJ, Guo C-A, Danai LV, Yawe JC, Gujja S, Edwards YJK, Czech MP. 2016. Endothelial mitogen-activated protein kinase kinase kinase kinase 4 is critical for lymphatic vascular development and function. Mol Cell Biol 36:1740–1749. doi:<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/MCB.01121-15">10.1128/MCB.01121-15</ext-link>
.</p>
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<pub-date pub-type="epreprint"><day>4</day>
<month>4</month>
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<pub-date pub-type="epub"><day>31</day>
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<pub-date pub-type="collection"><day>15</day>
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<volume>36</volume>
<issue>12</issue>
<fpage>1740</fpage>
<lpage>1749</lpage>
<history><date date-type="received"><day>1</day>
<month>1</month>
<year>2016</year>
</date>
<date date-type="rev-request"><day>2</day>
<month>2</month>
<year>2016</year>
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<date date-type="accepted"><day>30</day>
<month>3</month>
<year>2016</year>
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<permissions><copyright-statement>Copyright © 2016, American Society for Microbiology. All Rights Reserved.</copyright-statement>
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<abstract><p>The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.</p>
</abstract>
<funding-group><award-group id="award1"><funding-source id="gs1">HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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<principal-award-recipient>Rachel J. Roth Flach</principal-award-recipient>
<principal-award-recipient>Chang-An Guo</principal-award-recipient>
<principal-award-recipient>Laura V. Danai</principal-award-recipient>
<principal-award-recipient>Joseph Yawe</principal-award-recipient>
<principal-award-recipient>Sharvari Gujja</principal-award-recipient>
<principal-award-recipient>Yvonne JK Edwards</principal-award-recipient>
<principal-award-recipient>Michael P. Czech</principal-award-recipient>
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