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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling</title><author><name sortKey="Yang, Yan" sort="Yang, Yan" uniqKey="Yang Y" first="Yan" last="Yang">Yan Yang</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Xie, Peng" sort="Xie, Peng" uniqKey="Xie P" first="Peng" last="Xie">Peng Xie</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Opatowsky, Yarden" sort="Opatowsky, Yarden" uniqKey="Opatowsky Y" first="Yarden" last="Opatowsky">Yarden Opatowsky</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Schlessinger, Joseph" sort="Schlessinger, Joseph" uniqKey="Schlessinger J" first="Joseph" last="Schlessinger">Joseph Schlessinger</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20080685</idno><idno type="pmc">2836632</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836632</idno><idno type="RBID">PMC:2836632</idno><idno type="doi">10.1073/pnas.0914052107</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">003164</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003164</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling</title><author><name sortKey="Yang, Yan" sort="Yang, Yan" uniqKey="Yang Y" first="Yan" last="Yang">Yan Yang</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Xie, Peng" sort="Xie, Peng" uniqKey="Xie P" first="Peng" last="Xie">Peng Xie</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Opatowsky, Yarden" sort="Opatowsky, Yarden" uniqKey="Opatowsky Y" first="Yarden" last="Opatowsky">Yarden Opatowsky</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author><author><name sortKey="Schlessinger, Joseph" sort="Schlessinger, Joseph" uniqKey="Schlessinger J" first="Joseph" last="Schlessinger">Joseph Schlessinger</name><affiliation><nlm:aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 Å. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.</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">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20080685</article-id><article-id pub-id-type="pmc">2836632</article-id><article-id pub-id-type="publisher-id">200914052</article-id><article-id pub-id-type="doi">10.1073/pnas.0914052107</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biochemistry</subject></subj-group></subj-group></article-categories><title-group><article-title>Direct contacts between extracellular membrane-proximal domains are required for VEGF receptor activation and cell signaling</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Xie</surname><given-names>Peng</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Opatowsky</surname><given-names>Yarden</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Schlessinger</surname><given-names>Joseph</given-names></name><xref ref-type="aff" rid="aff1"></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1">Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence should be addressed. E-mail: <email>joseph.schlessinger@yale.edu</email>.</corresp><fn fn-type="con"><p>Contributed by Joseph Schlessinger, December 9, 2009 (sent for review November 27, 2009)</p></fn><fn fn-type="participating-researchers"><p>Author contributions: Y.Y. and J.S. designed research; Y.Y., P.X., and Y.O. performed research; Y.Y., P.X., Y.O., and J.S. analyzed data; and Y.Y. and J.S. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>2</day><month>2</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>11</day><month>1</month><year>2010</year></pub-date><volume>107</volume><issue>5</issue><fpage>1906</fpage><lpage>1911</lpage><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.0914052107.pdf"></self-uri><abstract><p>Structural analyses of the extracellular region of stem cell factor (SCF) receptor (also designated KIT) in complex with SCF revealed a sequence motif in a loop in the fourth Ig-like domain (D4) that is responsible for forming homotypic receptor contacts and for ligand-induced KIT activation and cell signaling. An identical motif was identified in the most membrane-proximal seventh Ig-like domain (D7) of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. In this report we demonstrate that ligand-induced tyrosine autophosphorylation and cell signaling via VEGFR1 or VEGFR2 harboring mutations in critical residues (Arg726 or Asp731) in D7 are strongly impaired. We also describe the crystal structure of D7 of VEGFR2 to a resolution of 2.7 Å. The structure shows that homotypic D7 contacts are mediated by salt bridges and van der Waals contacts formed between Arg726 of one protomer and Asp731 of the other protomer. The structure of D7 dimer is very similar to the structure of D4 dimers seen in the crystal structure of KIT extracellular region in complex with SCF. The high similarity between VEGFR D7 and KIT D4 in both structure and function provides further evidence for common ancestral origins of type III and type V RTKs. It also reveals a conserved mechanism for RTK activation and a novel target for pharmacological intervention of pathologically activated RTKs.</p></abstract><kwd-group><kwd>angiogenesis</kwd><kwd>cancer</kwd><kwd>phosphorylation</kwd><kwd>protein kinases</kwd><kwd>surface receptors</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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