Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1) requires Arf1, Arf6, and Rab11 GTPases
The soluble form of vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt1) is generated by alternative splicing of the FLT1 gene. Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with...
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| description | The soluble form of vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt1) is generated by alternative splicing of the FLT1 gene. Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [(35)S]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [(35)S]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA), a drug which blocks trafficking between the endoplasmic reticulum (ER) and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. This work is the first to report role of regulatory proteins involved in sFlt1 trafficking along the secretory pathway and may provide insights and new molecular targets for the modulation of sFlt-1 release during physiological and pathological conditions. |
| doi_str_mv | 10.1371/journal.pone.0044572 |
| format | Article |
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Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [(35)S]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [(35)S]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA), a drug which blocks trafficking between the endoplasmic reticulum (ER) and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. This work is the first to report role of regulatory proteins involved in sFlt1 trafficking along the secretory pathway and may provide insights and new molecular targets for the modulation of sFlt-1 release during physiological and pathological conditions.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0044572</identifier><identifier>PMID: 22962618</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ADP-Ribosylation Factor 1 - antagonists & inhibitors ; ADP-Ribosylation Factor 1 - genetics ; ADP-Ribosylation Factor 1 - metabolism ; ADP-Ribosylation Factors - antagonists & inhibitors ; ADP-Ribosylation Factors - genetics ; ADP-Ribosylation Factors - metabolism ; Alternative splicing ; Amino Acids - metabolism ; Biology ; Blood vessels ; Brefeldin A ; Brefeldin A - pharmacology ; Cell adhesion & migration ; Cell Line, Tumor ; Chronic kidney failure ; Cysteine ; Departments ; Ectopic expression ; Endoplasmic reticulum ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - genetics ; Endoplasmic Reticulum - metabolism ; Endothelial cells ; Flt1 protein ; G proteins ; Gene Expression - drug effects ; Golgi apparatus ; Golgi Apparatus - drug effects ; Golgi Apparatus - genetics ; Golgi Apparatus - metabolism ; Homeostasis ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypoxia ; Ligands ; Medicine ; Methionine ; Morphogenesis ; Plasmids ; Pre-eclampsia ; Preeclampsia ; Protein Structure, Tertiary ; Protein Synthesis Inhibitors - pharmacology ; Protein Transport - drug effects ; Proteins ; rab GTP-Binding Proteins - antagonists & inhibitors ; rab GTP-Binding Proteins - genetics ; rab GTP-Binding Proteins - metabolism ; Regulation ; Regulatory proteins ; RNA, Small Interfering - genetics ; Secretion ; Signal Transduction - drug effects ; siRNA ; Solubility ; Sulfur Radioisotopes ; Transfection ; Transport processes ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor Receptor-1 - genetics ; Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><ispartof>PloS one, 2012-09, Vol.7 (9), p.e44572</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Jung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Jung et al 2012 Jung et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-ec88912bc955dd701d822ebd6f0703877b8587690e0e887063495bfd3b4417b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433446/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433446/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22962618$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jung, Jae-Joon</creatorcontrib><creatorcontrib>Tiwari, Ajit</creatorcontrib><creatorcontrib>Inamdar, Shivangi M</creatorcontrib><creatorcontrib>Thomas, Christie P</creatorcontrib><creatorcontrib>Goel, Apollina</creatorcontrib><creatorcontrib>Choudhury, Amit</creatorcontrib><title>Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1) requires Arf1, Arf6, and Rab11 GTPases</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The soluble form of vascular endothelial growth factor receptor 1 (sVEGFR-1/sFlt1) is generated by alternative splicing of the FLT1 gene. Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [(35)S]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [(35)S]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA), a drug which blocks trafficking between the endoplasmic reticulum (ER) and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. 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drug effects</subject><subject>Endoplasmic Reticulum - genetics</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Endothelial cells</subject><subject>Flt1 protein</subject><subject>G proteins</subject><subject>Gene Expression - drug effects</subject><subject>Golgi apparatus</subject><subject>Golgi Apparatus - drug effects</subject><subject>Golgi Apparatus - genetics</subject><subject>Golgi Apparatus - metabolism</subject><subject>Homeostasis</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Ligands</subject><subject>Medicine</subject><subject>Methionine</subject><subject>Morphogenesis</subject><subject>Plasmids</subject><subject>Pre-eclampsia</subject><subject>Preeclampsia</subject><subject>Protein Structure, Tertiary</subject><subject>Protein Synthesis Inhibitors - pharmacology</subject><subject>Protein Transport - drug effects</subject><subject>Proteins</subject><subject>rab GTP-Binding Proteins - antagonists & inhibitors</subject><subject>rab GTP-Binding Proteins - genetics</subject><subject>rab GTP-Binding Proteins - metabolism</subject><subject>Regulation</subject><subject>Regulatory proteins</subject><subject>RNA, Small Interfering - genetics</subject><subject>Secretion</subject><subject>Signal Transduction - drug effects</subject><subject>siRNA</subject><subject>Solubility</subject><subject>Sulfur Radioisotopes</subject><subject>Transfection</subject><subject>Transport processes</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - genetics</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Ul1r2zAUNWNj7br9g7EJ9rJBk-rb8ssglCYrFDa6sFchy1eJg2Klkt3Rfz9lcUsDGwLpcnXOuUfiFMV7gqeEleRiE4bYGT_dhQ6mGHMuSvqiOCUVoxNJMXv5rD4p3qS0wVgwJeXr4oTSSlJJ1Gnx8BNshL4NHQoOpeCH2gO6N8kO3kQEXRP6NfjWeLSK4Xe_Rs7YPkQUwcJuXxD0Of26WsxvyUWa-558yVd3QxshoVl05Hy_y3NkugbdmpoQtFj-MAnS2-KVMz7Bu_E8K5bzq-Xlt8nN98X15exmYqWo-glYpSpCa1sJ0TQlJo2iFOpGOlxipsqyVkKVssKAQakSS8YrUbuG1ZyTsmZnxceD7M6HpMdPS5owKgWXWJCMuD4gmmA2ehfbrYkPOphW_22EuNIm9q31oLMwzvOYAcc4BVsLJbAjDpQUEkuXtb6O04Z6C42Fro_GH4ke33TtWq_CvWacMc5lFvg0CsRwN0Dq_2N5RK1MdtV2LmQxu22T1TORlbBUlGfU9B-ovBrYtjbHxrW5f0TgB4KNIaUI7sk4wXofukczeh86PYYu0z48f_QT6TFl7A9TBNIn</recordid><startdate>20120904</startdate><enddate>20120904</enddate><creator>Jung, Jae-Joon</creator><creator>Tiwari, Ajit</creator><creator>Inamdar, Shivangi M</creator><creator>Thomas, Christie P</creator><creator>Goel, Apollina</creator><creator>Choudhury, Amit</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120904</creationdate><title>Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1) requires Arf1, Arf6, and Rab11 GTPases</title><author>Jung, Jae-Joon ; Tiwari, Ajit ; Inamdar, Shivangi M ; Thomas, Christie P ; Goel, Apollina ; Choudhury, Amit</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c659t-ec88912bc955dd701d822ebd6f0703877b8587690e0e887063495bfd3b4417b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ADP-Ribosylation Factor 1 - 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Secretion of sFlt1 from endothelial cells plays an important role in blood vessel sprouting and morphogenesis. However, excess sFlt1 secretion is associated with diseases such as preeclampsia and chronic kidney disease. To date, the secretory transport process involved in the secretion of sFlt1 is poorly understood. In the present study, we investigated the itinerary of sFlt1 trafficking along the secretory pathway. To understand the timecourse of sFlt1 secretion, endothelial cells stably expressing sFlt1 were metabolically radiolabeled with [(35)S]-methionine and cysteine. Our results indicate that after initial synthesis the levels of secreted [(35)S]-sFlt1 in the extracellular medium peaks at 8 hours. Treatment with brefeldin A (BFA), a drug which blocks trafficking between the endoplasmic reticulum (ER) and the Golgi complex, inhibited extracellular release of sFlt1 suggesting that ER to Golgi and intra-Golgi trafficking of sFlt1 are essential for its secretion. Furthermore, we show that ectopic expression of dominant-negative mutant forms of Arf1, Arf6, and Rab11 as well as siRNA-mediated knockdown of these GTPases block secretion of sFlt1 during normoxic and hypoxic conditions suggesting role for these small GTPases. This work is the first to report role of regulatory proteins involved in sFlt1 trafficking along the secretory pathway and may provide insights and new molecular targets for the modulation of sFlt-1 release during physiological and pathological conditions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22962618</pmid><doi>10.1371/journal.pone.0044572</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1326546051 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | ADP-Ribosylation Factor 1 - antagonists & inhibitors ADP-Ribosylation Factor 1 - genetics ADP-Ribosylation Factor 1 - metabolism ADP-Ribosylation Factors - antagonists & inhibitors ADP-Ribosylation Factors - genetics ADP-Ribosylation Factors - metabolism Alternative splicing Amino Acids - metabolism Biology Blood vessels Brefeldin A Brefeldin A - pharmacology Cell adhesion & migration Cell Line, Tumor Chronic kidney failure Cysteine Departments Ectopic expression Endoplasmic reticulum Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - genetics Endoplasmic Reticulum - metabolism Endothelial cells Flt1 protein G proteins Gene Expression - drug effects Golgi apparatus Golgi Apparatus - drug effects Golgi Apparatus - genetics Golgi Apparatus - metabolism Homeostasis Human Umbilical Vein Endothelial Cells Humans Hypoxia Ligands Medicine Methionine Morphogenesis Plasmids Pre-eclampsia Preeclampsia Protein Structure, Tertiary Protein Synthesis Inhibitors - pharmacology Protein Transport - drug effects Proteins rab GTP-Binding Proteins - antagonists & inhibitors rab GTP-Binding Proteins - genetics rab GTP-Binding Proteins - metabolism Regulation Regulatory proteins RNA, Small Interfering - genetics Secretion Signal Transduction - drug effects siRNA Solubility Sulfur Radioisotopes Transfection Transport processes Vascular endothelial growth factor Vascular Endothelial Growth Factor Receptor-1 - genetics Vascular Endothelial Growth Factor Receptor-1 - metabolism |
| title | Secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR1/sFlt1) requires Arf1, Arf6, and Rab11 GTPases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T14%3A06%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Secretion%20of%20soluble%20vascular%20endothelial%20growth%20factor%20receptor%201%20(sVEGFR1/sFlt1)%20requires%20Arf1,%20Arf6,%20and%20Rab11%20GTPases&rft.jtitle=PloS%20one&rft.au=Jung,%20Jae-Joon&rft.date=2012-09-04&rft.volume=7&rft.issue=9&rft.spage=e44572&rft.pages=e44572-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0044572&rft_dat=%3Cgale_plos_%3EA543306824%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1326546051&rft_id=info:pmid/22962618&rft_galeid=A543306824&rft_doaj_id=oai_doaj_org_article_5bf0b853aef342ecb5850f1fe865606f&rfr_iscdi=true |