RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway
Vascular endothelial growth factor (VEGF) is vital to physiological as well as pathological angiogenesis, and regulates a variety of cellular functions, largely by activating its 2 receptors, fms-like tyrosine kinase (Flt1) and kinase domain receptor (KDR). KDR plays a critical role in the prolifera...
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| Veröffentlicht in: | The Journal of biological chemistry 2011-03, Vol.286 (11), p.9097-9106 |
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| creator | Wang, Feng Yamauchi, Mai Muramatsu, Masashi Osawa, Tsuyoshi Tsuchida, Rika Shibuya, Masabumi |
| description | Vascular endothelial growth factor (VEGF) is vital to physiological as well as pathological angiogenesis, and regulates a variety of cellular functions, largely by activating its 2 receptors, fms-like tyrosine kinase (Flt1) and kinase domain receptor (KDR). KDR plays a critical role in the proliferation of endothelial cells by controlling VEGF-induced phospholipase Cγ-protein kinase C (PLCγ-PKC) signaling. The function of Flt1, however, remains to be clarified. Recent evidence has indicated that Flt1 regulates the VEGF-triggered migration of endothelial cells and macrophages. Here, we show that RACK1, a ubiquitously expressed scaffolding protein, functions as an important regulator of this process. We found that RACK1 (receptor for activated protein kinase C 1) binds to Flt1 in vitro. When the endogenous expression of RACK1 was attenuated by RNA interference, the VEGF-driven migration was remarkably suppressed whereas the proliferation was unaffected in a stable Flt1-expressing cell line, AG1-G1-Flt1. Further, we demonstrated that the VEGF/Flt-mediated migration of AG1-G1-Flt1 cells occurred mainly via the activation of the PI3 kinase (PI3K)/Akt and Rac1 pathways, and that RACK1 plays a crucial regulatory role in promoting PI3K/Akt-Rac1 activation. |
| doi_str_mv | 10.1074/jbc.M110.165605 |
| format | Article |
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KDR plays a critical role in the proliferation of endothelial cells by controlling VEGF-induced phospholipase Cγ-protein kinase C (PLCγ-PKC) signaling. The function of Flt1, however, remains to be clarified. Recent evidence has indicated that Flt1 regulates the VEGF-triggered migration of endothelial cells and macrophages. Here, we show that RACK1, a ubiquitously expressed scaffolding protein, functions as an important regulator of this process. We found that RACK1 (receptor for activated protein kinase C 1) binds to Flt1 in vitro. When the endogenous expression of RACK1 was attenuated by RNA interference, the VEGF-driven migration was remarkably suppressed whereas the proliferation was unaffected in a stable Flt1-expressing cell line, AG1-G1-Flt1. Further, we demonstrated that the VEGF/Flt-mediated migration of AG1-G1-Flt1 cells occurred mainly via the activation of the PI3 kinase (PI3K)/Akt and Rac1 pathways, and that RACK1 plays a crucial regulatory role in promoting PI3K/Akt-Rac1 activation.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.165605</identifier><identifier>PMID: 21212275</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Akt PKB ; Angiogenesis ; Cell Line, Tumor ; Cell Migration ; Cell Movement - drug effects ; Cell Movement - physiology ; Enzyme Activation - drug effects ; Enzyme Activation - physiology ; Flt1(VEGFR1) ; GTP-Binding Proteins - genetics ; GTP-Binding Proteins - metabolism ; HEK293 Cells ; Humans ; MAP Kinases (MAPKs) ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phospholipase C gamma - genetics ; Phospholipase C gamma - metabolism ; PI 3-Kinase ; Protein Kinase C - genetics ; Protein Kinase C - metabolism ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; RACK1 (Receptor for Activated C-Kinase 1) ; Receptors for Activated C Kinase ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; RNA Interference ; RNA Interference (RNAi) ; Signal Transduction ; Signaling ; Vascular Endothelial Growth Factor (VEGF) ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor A - pharmacology ; Vascular Endothelial Growth Factor Receptor-1 - genetics ; Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><ispartof>The Journal of biological chemistry, 2011-03, Vol.286 (11), p.9097-9106</ispartof><rights>2011 © 2011 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2011 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-1f4e54031ac5b9d2b91a7cc80dd245b17313d012e298b2f6c3c854111be41f7c3</citedby><cites>FETCH-LOGICAL-c442t-1f4e54031ac5b9d2b91a7cc80dd245b17313d012e298b2f6c3c854111be41f7c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058986/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058986/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,725,778,782,883,27911,27912,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21212275$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Yamauchi, Mai</creatorcontrib><creatorcontrib>Muramatsu, Masashi</creatorcontrib><creatorcontrib>Osawa, Tsuyoshi</creatorcontrib><creatorcontrib>Tsuchida, Rika</creatorcontrib><creatorcontrib>Shibuya, Masabumi</creatorcontrib><title>RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Vascular endothelial growth factor (VEGF) is vital to physiological as well as pathological angiogenesis, and regulates a variety of cellular functions, largely by activating its 2 receptors, fms-like tyrosine kinase (Flt1) and kinase domain receptor (KDR). KDR plays a critical role in the proliferation of endothelial cells by controlling VEGF-induced phospholipase Cγ-protein kinase C (PLCγ-PKC) signaling. The function of Flt1, however, remains to be clarified. Recent evidence has indicated that Flt1 regulates the VEGF-triggered migration of endothelial cells and macrophages. Here, we show that RACK1, a ubiquitously expressed scaffolding protein, functions as an important regulator of this process. We found that RACK1 (receptor for activated protein kinase C 1) binds to Flt1 in vitro. When the endogenous expression of RACK1 was attenuated by RNA interference, the VEGF-driven migration was remarkably suppressed whereas the proliferation was unaffected in a stable Flt1-expressing cell line, AG1-G1-Flt1. Further, we demonstrated that the VEGF/Flt-mediated migration of AG1-G1-Flt1 cells occurred mainly via the activation of the PI3 kinase (PI3K)/Akt and Rac1 pathways, and that RACK1 plays a crucial regulatory role in promoting PI3K/Akt-Rac1 activation.</description><subject>Akt PKB</subject><subject>Angiogenesis</subject><subject>Cell Line, Tumor</subject><subject>Cell Migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Movement - physiology</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Activation - physiology</subject><subject>Flt1(VEGFR1)</subject><subject>GTP-Binding Proteins - genetics</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>MAP Kinases (MAPKs)</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phospholipase C gamma - genetics</subject><subject>Phospholipase C gamma - metabolism</subject><subject>PI 3-Kinase</subject><subject>Protein Kinase C - genetics</subject><subject>Protein Kinase C - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>RACK1 (Receptor for Activated C-Kinase 1)</subject><subject>Receptors for Activated C Kinase</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>RNA Interference</subject><subject>RNA Interference (RNAi)</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Vascular Endothelial Growth Factor (VEGF)</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascular Endothelial Growth Factor A - pharmacology</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - genetics</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtPAyEUhYnRaH2s3Rl2rsZyeXSGjUnTWDVqNEaNO8IwTEWnMwq0xn8vzajRhbAgFz4Ol3MQ2gdyBCTnw-fSHF3BqhqJERFraACkYBkT8LiOBoRQyCQVxRbaDuGZpMElbKItCmnSXAzQw-14cgH41s4WjY424IeT0-lw2kTI5rZyaavCE9s0-MrNvI6ua_HSaTw20S37squxxjfn7GI4fon4Rsend_2xizZq3QS797XuoPvpyd3kLLu8Pj2fjC8zwzmNGdTcCk4YaCNKWdFSgs6NKUhVUS5KyBmwigC1VBYlrUeGmUJwACgthzo3bAcd97qvizL1a2wbvW7Uq3dz7T9Up536e9K6JzXrlooRUchilAQOvwR897awIaq5CyZ9WLe2WwRVCMklpUQmctiTxncheFv_vAJErcJQKQy1CkP1YaQbB7-b--G_3U-A7AGbLFo661UwzrYmGe-tiarq3L_in4Iol1A</recordid><startdate>20110318</startdate><enddate>20110318</enddate><creator>Wang, Feng</creator><creator>Yamauchi, Mai</creator><creator>Muramatsu, Masashi</creator><creator>Osawa, Tsuyoshi</creator><creator>Tsuchida, Rika</creator><creator>Shibuya, Masabumi</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110318</creationdate><title>RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway</title><author>Wang, Feng ; Yamauchi, Mai ; Muramatsu, Masashi ; Osawa, Tsuyoshi ; Tsuchida, Rika ; Shibuya, Masabumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-1f4e54031ac5b9d2b91a7cc80dd245b17313d012e298b2f6c3c854111be41f7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Akt PKB</topic><topic>Angiogenesis</topic><topic>Cell Line, Tumor</topic><topic>Cell Migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell Movement - physiology</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Activation - physiology</topic><topic>Flt1(VEGFR1)</topic><topic>GTP-Binding Proteins - genetics</topic><topic>GTP-Binding Proteins - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>MAP Kinases (MAPKs)</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phospholipase C gamma - genetics</topic><topic>Phospholipase C gamma - metabolism</topic><topic>PI 3-Kinase</topic><topic>Protein Kinase C - genetics</topic><topic>Protein Kinase C - metabolism</topic><topic>Protein Structure, Tertiary</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>RACK1 (Receptor for Activated C-Kinase 1)</topic><topic>Receptors for Activated C Kinase</topic><topic>Receptors, Cell Surface - genetics</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>RNA Interference</topic><topic>RNA Interference (RNAi)</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Vascular Endothelial Growth Factor (VEGF)</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascular Endothelial Growth Factor A - pharmacology</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - genetics</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Yamauchi, Mai</creatorcontrib><creatorcontrib>Muramatsu, Masashi</creatorcontrib><creatorcontrib>Osawa, Tsuyoshi</creatorcontrib><creatorcontrib>Tsuchida, Rika</creatorcontrib><creatorcontrib>Shibuya, Masabumi</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Feng</au><au>Yamauchi, Mai</au><au>Muramatsu, Masashi</au><au>Osawa, Tsuyoshi</au><au>Tsuchida, Rika</au><au>Shibuya, Masabumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-03-18</date><risdate>2011</risdate><volume>286</volume><issue>11</issue><spage>9097</spage><epage>9106</epage><pages>9097-9106</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Vascular endothelial growth factor (VEGF) is vital to physiological as well as pathological angiogenesis, and regulates a variety of cellular functions, largely by activating its 2 receptors, fms-like tyrosine kinase (Flt1) and kinase domain receptor (KDR). KDR plays a critical role in the proliferation of endothelial cells by controlling VEGF-induced phospholipase Cγ-protein kinase C (PLCγ-PKC) signaling. The function of Flt1, however, remains to be clarified. Recent evidence has indicated that Flt1 regulates the VEGF-triggered migration of endothelial cells and macrophages. Here, we show that RACK1, a ubiquitously expressed scaffolding protein, functions as an important regulator of this process. We found that RACK1 (receptor for activated protein kinase C 1) binds to Flt1 in vitro. When the endogenous expression of RACK1 was attenuated by RNA interference, the VEGF-driven migration was remarkably suppressed whereas the proliferation was unaffected in a stable Flt1-expressing cell line, AG1-G1-Flt1. Further, we demonstrated that the VEGF/Flt-mediated migration of AG1-G1-Flt1 cells occurred mainly via the activation of the PI3 kinase (PI3K)/Akt and Rac1 pathways, and that RACK1 plays a crucial regulatory role in promoting PI3K/Akt-Rac1 activation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21212275</pmid><doi>10.1074/jbc.M110.165605</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Akt PKB Angiogenesis Cell Line, Tumor Cell Migration Cell Movement - drug effects Cell Movement - physiology Enzyme Activation - drug effects Enzyme Activation - physiology Flt1(VEGFR1) GTP-Binding Proteins - genetics GTP-Binding Proteins - metabolism HEK293 Cells Humans MAP Kinases (MAPKs) Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phospholipase C gamma - genetics Phospholipase C gamma - metabolism PI 3-Kinase Protein Kinase C - genetics Protein Kinase C - metabolism Protein Structure, Tertiary Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism RACK1 (Receptor for Activated C-Kinase 1) Receptors for Activated C Kinase Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism RNA Interference RNA Interference (RNAi) Signal Transduction Signaling Vascular Endothelial Growth Factor (VEGF) Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor A - pharmacology Vascular Endothelial Growth Factor Receptor-1 - genetics Vascular Endothelial Growth Factor Receptor-1 - metabolism |
| title | RACK1 Regulates VEGF/Flt1-mediated Cell Migration via Activation of a PI3K/Akt Pathway |
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