The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis
Identifieur interne : 000B61 ( Pmc/Corpus ); précédent : 000B60; suivant : 000B62The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis
Auteurs : Geraldine Siegfried ; Ajoy Basak ; James A. Cromlish ; Suzanne Benjannet ; Jadwiga Marcinkiewicz ; Michel Chrétien ; Nabil G. Seidah ; Abdel-Majid KhatibSource :
- Journal of Clinical Investigation [ 0021-9738 ] ; 2003.
Abstract
The secretory factor VEGF-C has been directly implicated in various physiological processes during embryogenesis and human cancers. However, the importance of the conversion of its precursor proVEGF-C to mature VEGF-C in tumorigenesis, and vessel formation and the identity of the protease(s) that regulate these processes is/are not known. The intracellular processing of proVEGF-C that occurs within the dibasic motif HSIIRR227SL suggests the involvement of the proprotein convertases (PCs) in this process. In addition, furin and VEGF-C were found to be coordinately expressed in adult mouse tissues. Cotransfection of the furin-deficient colon carcinoma cell line LoVo with proVEGF-C and different PC members revealed that furin, PC5, and PC7 are candidate VEGF-C convertases. This finding is consistent with the in vitro digestions of an internally quenched synthetic fluorogenic peptide mimicking the cleavage site of proVEGF-C (220Q-VHSIIRR↓SLP230). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of α2-macroglobulin and α1-antitrypsin. Subcutaneous injection of CHO cells stably expressing VEGF-C into nude mice enhanced angiogenesis and lymphangiogenesis, but not tumor growth. In contrast, expression of proVEGF-C obtained following mutation of the cleavage site (HSIIRR227SL to HSII
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DOI: 10.1172/JCI200317220
PubMed: 12782675
PubMed Central: 156106
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PMC:156106Le document en format XML
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<author><name sortKey="Cromlish, James A" sort="Cromlish, James A" uniqKey="Cromlish J" first="James A." last="Cromlish">James A. Cromlish</name>
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<series><title level="j">Journal of Clinical Investigation</title>
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<front><div type="abstract" xml:lang="en"><p>The secretory factor VEGF-C has been directly implicated in various physiological processes during embryogenesis and human cancers. However, the importance of the conversion of its precursor proVEGF-C to mature VEGF-C in tumorigenesis, and vessel formation and the identity of the protease(s) that regulate these processes is/are not known. The intracellular processing of proVEGF-C that occurs within the dibasic motif HSIIRR<sup>227</sup>
SL suggests the involvement of the proprotein convertases (PCs) in this process. In addition, furin and VEGF-C were found to be coordinately expressed in adult mouse tissues. Cotransfection of the furin-deficient colon carcinoma cell line LoVo with proVEGF-C and different PC members revealed that furin, PC5, and PC7 are candidate VEGF-C convertases. This finding is consistent with the in vitro digestions of an internally quenched synthetic fluorogenic peptide mimicking the cleavage site of proVEGF-C (<sup>220</sup>
Q-VHSIIRR↓SLP<sup>230</sup>
). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of α2-macroglobulin and α1-antitrypsin. Subcutaneous injection of CHO cells stably expressing VEGF-C into nude mice enhanced angiogenesis and lymphangiogenesis, but not tumor growth. In contrast, expression of proVEGF-C obtained following mutation of the cleavage site (HSIIRR<sup>227</sup>
SL to HSII<underline>SS</underline>
<sup>227</sup>
SL) inhibits angiogenesis and lymphangiogenesis as well as tumor growth. Our findings demonstrate the processing of proVEGF-C by PCs and highlight the potential use of PC inhibitors as agents for inhibiting malignancies induced by VEGF-C.</p>
</div>
</front>
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<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 Clin Invest</journal-id>
<journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id>
<journal-title>Journal of Clinical Investigation</journal-title>
<issn pub-type="ppub">0021-9738</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
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<article-id pub-id-type="pmc">156106</article-id>
<article-id pub-id-type="publisher-id">17220</article-id>
<article-id pub-id-type="doi">10.1172/JCI200317220</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Siegfried</surname>
<given-names>Geraldine</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Basak</surname>
<given-names>Ajoy</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cromlish</surname>
<given-names>James A.</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Benjannet</surname>
<given-names>Suzanne</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Marcinkiewicz</surname>
<given-names>Jadwiga</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chrétien</surname>
<given-names>Michel</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Seidah</surname>
<given-names>Nabil G.</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Khatib</surname>
<given-names>Abdel-Majid</given-names>
</name>
<xref ref-type="aff" rid="N0x9626200.0x9af66f8">2</xref>
</contrib>
</contrib-group>
<aff id="N0x9626200.0x9af66f8"><label>1</label>
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada<label>2</label>
Regional Protein Chemistry Centre, Diseases of Aging Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada</aff>
<author-notes><fn><p>Address correspondence to: Abdel-Majid Khatib, Regional Protein Chemistry Centre, Diseases of Ageing Unit, Ottawa Health Research Institute, Loeb Building, 725 Parkdale Avenue, Ottawa, Ontario K1Y 4E9, Canada. Phone: (613) 798-5555 ext. 16086; Fax: (613) 761-4355; E-mail: <email>mkhatib@ohri.ca</email>
.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>1</day>
<month>6</month>
<year>2003</year>
</pub-date>
<volume>111</volume>
<issue>11</issue>
<fpage>1723</fpage>
<lpage>1732</lpage>
<history><date date-type="received"><day>22</day>
<month>10</month>
<year>2002</year>
</date>
<date date-type="accepted"><day>19</day>
<month>3</month>
<year>2003</year>
</date>
</history>
<copyright-statement>Copyright © 2003, American Society for Clinical Investigation</copyright-statement>
<copyright-year>2003</copyright-year>
<abstract><p>The secretory factor VEGF-C has been directly implicated in various physiological processes during embryogenesis and human cancers. However, the importance of the conversion of its precursor proVEGF-C to mature VEGF-C in tumorigenesis, and vessel formation and the identity of the protease(s) that regulate these processes is/are not known. The intracellular processing of proVEGF-C that occurs within the dibasic motif HSIIRR<sup>227</sup>
SL suggests the involvement of the proprotein convertases (PCs) in this process. In addition, furin and VEGF-C were found to be coordinately expressed in adult mouse tissues. Cotransfection of the furin-deficient colon carcinoma cell line LoVo with proVEGF-C and different PC members revealed that furin, PC5, and PC7 are candidate VEGF-C convertases. This finding is consistent with the in vitro digestions of an internally quenched synthetic fluorogenic peptide mimicking the cleavage site of proVEGF-C (<sup>220</sup>
Q-VHSIIRR↓SLP<sup>230</sup>
). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of α2-macroglobulin and α1-antitrypsin. Subcutaneous injection of CHO cells stably expressing VEGF-C into nude mice enhanced angiogenesis and lymphangiogenesis, but not tumor growth. In contrast, expression of proVEGF-C obtained following mutation of the cleavage site (HSIIRR<sup>227</sup>
SL to HSII<underline>SS</underline>
<sup>227</sup>
SL) inhibits angiogenesis and lymphangiogenesis as well as tumor growth. Our findings demonstrate the processing of proVEGF-C by PCs and highlight the potential use of PC inhibitors as agents for inhibiting malignancies induced by VEGF-C.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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