Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity*
Identifieur interne : 002E94 ( Pmc/Corpus ); précédent : 002E93; suivant : 002E95Mutation 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
Links to Exploration step
PMC:4110307Le document en format XML
<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></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></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><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><idno type="wicri:Area/Pmc/Corpus">002E94</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002E94</idno></publicationStmt><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></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/LymphedemaV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002E94 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 002E94 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= LymphedemaV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:4110307
|texte= Mutation of Threonine 34 in Mouse Podoplanin-Fc Reduces CLEC-2 Binding and Toxicity in Vivo While Retaining Anti-lymphangiogenic Activity*
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:24907275" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a LymphedemaV1
| This area was generated with Dilib version V0.6.31. |  |