Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity*
Identifieur interne : 002E93 ( Pmc/Curation ); précédent : 002E92; suivant : 002E94Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity*
Auteurs : Roberta Bianchi ; Eliane Fischer ; Don Yuen ; Ellen Ernst ; Alexandra M. Ochsenbein ; Lu Chen ; Vivianne I. Otto ; Michael DetmarSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2014.
Abstract
Url:
DOI: 10.1074/jbc.M114.550525
PubMed: 24907275
PubMed Central: 4110307
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity <italic>in Vivo</italic>
While Retaining Anti-lymphangiogenic Activity<xref ref-type="fn" rid="FN1">*</xref>
</title>
<author><name sortKey="Bianchi, Roberta" sort="Bianchi, Roberta" uniqKey="Bianchi R" first="Roberta" last="Bianchi">Roberta Bianchi</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
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<author><name sortKey="Fischer, Eliane" sort="Fischer, Eliane" uniqKey="Fischer E" first="Eliane" last="Fischer">Eliane Fischer</name>
<affiliation><nlm:aff id="aff2"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yuen, Don" sort="Yuen, Don" uniqKey="Yuen D" first="Don" last="Yuen">Don Yuen</name>
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<author><name sortKey="Ernst, Ellen" sort="Ernst, Ellen" uniqKey="Ernst E" first="Ellen" last="Ernst">Ellen Ernst</name>
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</affiliation>
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<author><name sortKey="Ochsenbein, Alexandra M" sort="Ochsenbein, Alexandra M" uniqKey="Ochsenbein A" first="Alexandra M." last="Ochsenbein">Alexandra M. Ochsenbein</name>
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<author><name sortKey="Chen, Lu" sort="Chen, Lu" uniqKey="Chen L" first="Lu" last="Chen">Lu Chen</name>
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</affiliation>
</author>
<author><name sortKey="Otto, Vivianne I" sort="Otto, Vivianne I" uniqKey="Otto V" first="Vivianne I." last="Otto">Vivianne I. Otto</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
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<idno type="pmid">24907275</idno>
<idno type="pmc">4110307</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110307</idno>
<idno type="RBID">PMC:4110307</idno>
<idno type="doi">10.1074/jbc.M114.550525</idno>
<date when="2014">2014</date>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity <italic>in Vivo</italic>
While Retaining Anti-lymphangiogenic Activity<xref ref-type="fn" rid="FN1">*</xref>
</title>
<author><name sortKey="Bianchi, Roberta" sort="Bianchi, Roberta" uniqKey="Bianchi R" first="Roberta" last="Bianchi">Roberta Bianchi</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fischer, Eliane" sort="Fischer, Eliane" uniqKey="Fischer E" first="Eliane" last="Fischer">Eliane Fischer</name>
<affiliation><nlm:aff id="aff2"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yuen, Don" sort="Yuen, Don" uniqKey="Yuen D" first="Don" last="Yuen">Don Yuen</name>
<affiliation><nlm:aff id="aff3"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ernst, Ellen" sort="Ernst, Ellen" uniqKey="Ernst E" first="Ellen" last="Ernst">Ellen Ernst</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ochsenbein, Alexandra M" sort="Ochsenbein, Alexandra M" uniqKey="Ochsenbein A" first="Alexandra M." last="Ochsenbein">Alexandra M. Ochsenbein</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chen, Lu" sort="Chen, Lu" uniqKey="Chen L" first="Lu" last="Chen">Lu Chen</name>
<affiliation><nlm:aff id="aff3"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Otto, Vivianne I" sort="Otto, Vivianne I" uniqKey="Otto V" first="Vivianne I." last="Otto">Vivianne I. Otto</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Biological Chemistry</title>
<idno type="ISSN">0021-9258</idno>
<idno type="eISSN">1083-351X</idno>
<imprint><date when="2014">2014</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p><bold>Background:</bold>
Podoplanin-Fc inhibits lymphangiogenesis, but also causes a bleeding disorder by binding to CLEC-2 expressed on platelets.</p>
<p><bold>Results:</bold>
Mutation of threonine 34 in mouse Pdpn-Fc reduces 30-fold the binding to CLEC-2 and does not hamper its anti-lymphangiogenic activity.</p>
<p><bold>Conclusion:</bold>
PdpnT34A-Fc is an active lymphangiogenesis inhibitor with a better tolerability.</p>
<p><bold>Significance:</bold>
Mutagenesis of Pdpn-Fc is a valid approach to improve this tool for anti-lymphangiogenic therapy.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biol Chem</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Biol. Chem</journal-id>
<journal-id journal-id-type="hwp">jbc</journal-id>
<journal-id journal-id-type="pmc">jbc</journal-id>
<journal-id journal-id-type="publisher-id">JBC</journal-id>
<journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title>
</journal-title-group>
<issn pub-type="ppub">0021-9258</issn>
<issn pub-type="epub">1083-351X</issn>
<publisher><publisher-name>American Society for Biochemistry and Molecular Biology</publisher-name>
<publisher-loc>9650 Rockville Pike, Bethesda, MD 20814, U.S.A.</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24907275</article-id>
<article-id pub-id-type="pmc">4110307</article-id>
<article-id pub-id-type="publisher-id">M114.550525</article-id>
<article-id pub-id-type="doi">10.1074/jbc.M114.550525</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Cell Biology</subject>
</subj-group>
</article-categories>
<title-group><article-title>Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity <italic>in Vivo</italic>
While Retaining Anti-lymphangiogenic Activity<xref ref-type="fn" rid="FN1">*</xref>
</article-title>
<alt-title alt-title-type="short">mPdpnT34A-Fc as an Improved Lymphangiogenesis Inhibitor</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Bianchi</surname>
<given-names>Roberta</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fischer</surname>
<given-names>Eliane</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yuen</surname>
<given-names>Don</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>¶</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ernst</surname>
<given-names>Ellen</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ochsenbein</surname>
<given-names>Alexandra M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Lu</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>¶</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Otto</surname>
<given-names>Vivianne I.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Detmar</surname>
<given-names>Michael</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>‡</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
</xref>
</contrib>
<aff id="aff1">From the<label>‡</label>
Institute of Pharmaceutical Sciences, ETH Zurich, 8093 Zurich, Switzerland,</aff>
<aff id="aff2">the<label>§</label>
Center for Radiopharmaceutical Sciences, Paul Scherrer Institute PSI, 5232 Villigen, Switzerland, and</aff>
<aff id="aff3">the<label>¶</label>
Center for Eye Disease and Development, Program in Vision Science and School of Optometry, University of California at Berkeley, Berkeley, California 94720</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>1</label>
To whom correspondence should be addressed: <addr-line>ETH Zurich, Vladimir-Prelog-Weg 3, HCI H303, CH-8093 Zurich, Switzerland.</addr-line>
Tel.: <phone>41-44-633-7361</phone>
; Fax: <fax>41-44-633-1364</fax>
; E-mail: <email>michael.detmar@pharma.ethz.ch</email>
.</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>25</day>
<month>7</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>6</day>
<month>6</month>
<year>2014</year>
</pub-date>
<volume>289</volume>
<issue>30</issue>
<fpage>21016</fpage>
<lpage>21027</lpage>
<history><date date-type="received"><day>15</day>
<month>1</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>20</day>
<month>5</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.</copyright-statement>
<copyright-year>2014</copyright-year>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zbc03014021016.pdf"></self-uri>
<abstract abstract-type="teaser"><p><bold>Background:</bold>
Podoplanin-Fc inhibits lymphangiogenesis, but also causes a bleeding disorder by binding to CLEC-2 expressed on platelets.</p>
<p><bold>Results:</bold>
Mutation of threonine 34 in mouse Pdpn-Fc reduces 30-fold the binding to CLEC-2 and does not hamper its anti-lymphangiogenic activity.</p>
<p><bold>Conclusion:</bold>
PdpnT34A-Fc is an active lymphangiogenesis inhibitor with a better tolerability.</p>
<p><bold>Significance:</bold>
Mutagenesis of Pdpn-Fc is a valid approach to improve this tool for anti-lymphangiogenic therapy.</p>
</abstract>
<abstract><p>The lymphatic system plays an important role in cancer metastasis and inhibition of lymphangiogenesis could be valuable in fighting cancer dissemination. Podoplanin (Pdpn) is a small, transmembrane glycoprotein expressed on the surface of lymphatic endothelial cells (LEC). During mouse development, binding of Pdpn to the C-type lectin-like receptor 2 (CLEC-2) on platelets is critical for the separation of the lymphatic and blood vascular systems. Competitive inhibition of Pdpn functions with a soluble form of the protein, Pdpn-Fc, leads to reduced lymphangiogenesis <italic>in vitro</italic>
and <italic>in vivo</italic>
. However, the transgenic overexpression of human Pdpn-Fc in mouse skin causes disseminated intravascular coagulation due to platelet activation via CLEC-2. In the present study, we produced and characterized a mutant form of mouse Pdpn-Fc, in which threonine 34, which is considered essential for CLEC-2 binding, was mutated to alanine (PdpnT34A-Fc). Indeed, PdpnT34A-Fc displayed a 30-fold reduced binding affinity for CLEC-2 compared with Pdpn-Fc. This also translated into fewer side effects due to platelet activation <italic>in vivo</italic>
. Mice showed less prolonged bleeding time and fewer embolized vessels in the liver, when PdpnT34A-Fc was injected intravenously. However, PdpnT34A-Fc was still as active as wild-type Pdpn-Fc in inhibiting lymphangiogenesis <italic>in vitro</italic>
and also inhibited lymphangiogenesis <italic>in vivo</italic>
. These data suggest that the function of Pdpn in lymphangiogenesis does not depend on threonine 34 in the CLEC-2 binding domain and that PdpnT34A-Fc might be an improved inhibitor of lymphangiogenesis with fewer toxic side effects.</p>
</abstract>
<kwd-group><kwd>Glycosylation</kwd>
<kwd>Lymphangiogenesis</kwd>
<kwd>Mutagenesis</kwd>
<kwd>Platelet</kwd>
<kwd>Recombinant Protein Expression</kwd>
<kwd>CLEC-2</kwd>
<kwd>Podoplanin</kwd>
</kwd-group>
<funding-group><award-group><funding-source id="CS100">National Institutes of Health</funding-source>
<award-id rid="CS100">31003A-130627</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
</record>
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