Regulation of vesicle transport and cell motility by Golgi-localized Dbs
DBS/MCF2L has been recently identified as a risk locus for osteoarthritis. It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms,...
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description | DBS/MCF2L has been recently identified as a risk locus for osteoarthritis. It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms, a 130 kDa form (Dbs-130) that is localized to the Golgi complex, and an 80 kDa form (Dbs-80) that is localized to the endoplasmic reticulum (ER). We have previously described an inhibitor that binds to the RhoGEF domain of Dbs and blocks its transforming activity. Here we show that the inhibitor localizes to the Golgi, where it specifically interacts with Dbs-130. Inhibition of endogenous Dbs-130 activity is associated with reduced levels of activated Cdc42, enlarged Golgi, and resistance to Brefeldin A-mediated Golgi dispersal, suggesting a role for Dbs in vesicle transport. Cells treated with the inhibitor exhibit normal protein transport from the ER to the Golgi, but are defective in transport from the Golgi to the plasma membrane. Inhibition of Dbs-130 in MDA-MB-231 human breast tumor cells limits motility in both transwell and wound healing assays, but appears to have no effect on the organization of the microtubule cytoskeleton. The reduced motility is associated with a failure to reorient the Golgi toward the leading edge. This is consistent with the Golgi localization, and suggests that the Dbs-130 regulates aspects of the secretory pathway that are required to support cell polarization during directed migration. |
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It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms, a 130 kDa form (Dbs-130) that is localized to the Golgi complex, and an 80 kDa form (Dbs-80) that is localized to the endoplasmic reticulum (ER). We have previously described an inhibitor that binds to the RhoGEF domain of Dbs and blocks its transforming activity. Here we show that the inhibitor localizes to the Golgi, where it specifically interacts with Dbs-130. Inhibition of endogenous Dbs-130 activity is associated with reduced levels of activated Cdc42, enlarged Golgi, and resistance to Brefeldin A-mediated Golgi dispersal, suggesting a role for Dbs in vesicle transport. Cells treated with the inhibitor exhibit normal protein transport from the ER to the Golgi, but are defective in transport from the Golgi to the plasma membrane. Inhibition of Dbs-130 in MDA-MB-231 human breast tumor cells limits motility in both transwell and wound healing assays, but appears to have no effect on the organization of the microtubule cytoskeleton. The reduced motility is associated with a failure to reorient the Golgi toward the leading edge. This is consistent with the Golgi localization, and suggests that the Dbs-130 regulates aspects of the secretory pathway that are required to support cell polarization during directed migration.</description><identifier>ISSN: 2154-1248</identifier><identifier>EISSN: 2154-1256</identifier><identifier>DOI: 10.4161/sgtp.28570</identifier><identifier>PMID: 25483302</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Biological Transport - drug effects ; breast cancer ; Brefeldin A - pharmacology ; Carrier Proteins - chemistry ; Carrier Proteins - metabolism ; cdc42 GTP-Binding Protein - metabolism ; Cell Line, Tumor ; cell motility ; Cell Movement - drug effects ; Cytoskeleton - metabolism ; Dbs ; Endoplasmic Reticulum - metabolism ; Golgi Apparatus - drug effects ; Golgi Apparatus - metabolism ; golgi complex ; guanine nucleotide exchange factor ; Guanine Nucleotide Exchange Factors - antagonists & inhibitors ; Guanine Nucleotide Exchange Factors - chemistry ; Guanine Nucleotide Exchange Factors - metabolism ; HeLa Cells ; Humans ; MCF2L ; osteoarthritis ; Protein Binding ; Protein Isoforms - antagonists & inhibitors ; Protein Isoforms - chemistry ; Protein Isoforms - metabolism ; Protein Structure, Tertiary ; Research Paper ; Rho ; RNA Interference ; RNA, Small Interfering - metabolism ; Secretory Vesicles - metabolism</subject><ispartof>Small GTPases, 2014-10, Vol.5 (4), p.1-12</ispartof><rights>2014 Taylor & Francis Group, LLC 2014</rights><rights>2014 Taylor & Francis Group, LLC 2014 Taylor & Francis Group, LLC</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3390-427e9b5457fcc4b9b72cc4d32e3d43da13c4cbddd670d123cb9fb66ad7de447b3</citedby><cites>FETCH-LOGICAL-c3390-427e9b5457fcc4b9b72cc4d32e3d43da13c4cbddd670d123cb9fb66ad7de447b3</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/PMC4601361/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601361/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25483302$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fitzpatrick, Ethan R</creatorcontrib><creatorcontrib>Hu, Tinghui</creatorcontrib><creatorcontrib>Ciccarelli, Bryan T</creatorcontrib><creatorcontrib>Whitehead, Ian P</creatorcontrib><title>Regulation of vesicle transport and cell motility by Golgi-localized Dbs</title><title>Small GTPases</title><addtitle>Small GTPases</addtitle><description>DBS/MCF2L has been recently identified as a risk locus for osteoarthritis. It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms, a 130 kDa form (Dbs-130) that is localized to the Golgi complex, and an 80 kDa form (Dbs-80) that is localized to the endoplasmic reticulum (ER). We have previously described an inhibitor that binds to the RhoGEF domain of Dbs and blocks its transforming activity. Here we show that the inhibitor localizes to the Golgi, where it specifically interacts with Dbs-130. Inhibition of endogenous Dbs-130 activity is associated with reduced levels of activated Cdc42, enlarged Golgi, and resistance to Brefeldin A-mediated Golgi dispersal, suggesting a role for Dbs in vesicle transport. Cells treated with the inhibitor exhibit normal protein transport from the ER to the Golgi, but are defective in transport from the Golgi to the plasma membrane. Inhibition of Dbs-130 in MDA-MB-231 human breast tumor cells limits motility in both transwell and wound healing assays, but appears to have no effect on the organization of the microtubule cytoskeleton. The reduced motility is associated with a failure to reorient the Golgi toward the leading edge. This is consistent with the Golgi localization, and suggests that the Dbs-130 regulates aspects of the secretory pathway that are required to support cell polarization during directed migration.</description><subject>Biological Transport - drug effects</subject><subject>breast cancer</subject><subject>Brefeldin A - pharmacology</subject><subject>Carrier Proteins - chemistry</subject><subject>Carrier Proteins - metabolism</subject><subject>cdc42 GTP-Binding Protein - metabolism</subject><subject>Cell Line, Tumor</subject><subject>cell motility</subject><subject>Cell Movement - drug effects</subject><subject>Cytoskeleton - metabolism</subject><subject>Dbs</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Golgi Apparatus - drug effects</subject><subject>Golgi Apparatus - metabolism</subject><subject>golgi complex</subject><subject>guanine nucleotide exchange factor</subject><subject>Guanine Nucleotide Exchange Factors - antagonists & inhibitors</subject><subject>Guanine Nucleotide Exchange Factors - chemistry</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>MCF2L</subject><subject>osteoarthritis</subject><subject>Protein Binding</subject><subject>Protein Isoforms - antagonists & inhibitors</subject><subject>Protein Isoforms - chemistry</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Research Paper</subject><subject>Rho</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Secretory Vesicles - metabolism</subject><issn>2154-1248</issn><issn>2154-1256</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkNtKAzEQhoMottTe-ACSSxG2bk6b7o0gHlqhIIheh5y2RrKbmmwr9end2loUzM0E5uOfmQ-AU5SPKCrQZZq3ixEeM54fgD5GjGYIs-Jw_6fjHhim9JZ3j5aYl-QY9DCjY0Jy3AfTJztfetm60MBQwZVNTnsL2yibtAixhbIxUFvvYR1a5127hmoNJ8HPXeaDlt59WgNvVToBR5X0yQ53dQBe7u-eb6bZ7HHycHM9yzQhZZ5RzG2pGGW80pqqUnHcVUOwJYYSIxHRVCtjTMFzgzDRqqxUUUjDjaWUKzIAV9vcxVLV1mjbdLt6sYiulnEtgnTib6dxr2IeVoIWOSIF6gLOdwExvC9takXt0uZC2diwTAIVhDNOKRt36MUW1TGkFG21H4NysbEvNvbFt_0OPvu92B79cd0BbAu4pgqxlh8heiNaufYhVp1v7ZIg_wR_AdOqlMo</recordid><startdate>20141002</startdate><enddate>20141002</enddate><creator>Fitzpatrick, Ethan R</creator><creator>Hu, Tinghui</creator><creator>Ciccarelli, Bryan T</creator><creator>Whitehead, Ian P</creator><general>Taylor & Francis</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141002</creationdate><title>Regulation of vesicle transport and cell motility by Golgi-localized Dbs</title><author>Fitzpatrick, Ethan R ; Hu, Tinghui ; Ciccarelli, Bryan T ; Whitehead, Ian P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3390-427e9b5457fcc4b9b72cc4d32e3d43da13c4cbddd670d123cb9fb66ad7de447b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Biological Transport - drug effects</topic><topic>breast cancer</topic><topic>Brefeldin A - pharmacology</topic><topic>Carrier Proteins - chemistry</topic><topic>Carrier Proteins - metabolism</topic><topic>cdc42 GTP-Binding Protein - metabolism</topic><topic>Cell Line, Tumor</topic><topic>cell motility</topic><topic>Cell Movement - drug effects</topic><topic>Cytoskeleton - metabolism</topic><topic>Dbs</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Golgi Apparatus - drug effects</topic><topic>Golgi Apparatus - metabolism</topic><topic>golgi complex</topic><topic>guanine nucleotide exchange factor</topic><topic>Guanine Nucleotide Exchange Factors - antagonists & inhibitors</topic><topic>Guanine Nucleotide Exchange Factors - chemistry</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>MCF2L</topic><topic>osteoarthritis</topic><topic>Protein Binding</topic><topic>Protein Isoforms - antagonists & inhibitors</topic><topic>Protein Isoforms - chemistry</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein Structure, Tertiary</topic><topic>Research Paper</topic><topic>Rho</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Secretory Vesicles - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fitzpatrick, Ethan R</creatorcontrib><creatorcontrib>Hu, Tinghui</creatorcontrib><creatorcontrib>Ciccarelli, Bryan T</creatorcontrib><creatorcontrib>Whitehead, Ian P</creatorcontrib><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>Small GTPases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fitzpatrick, Ethan R</au><au>Hu, Tinghui</au><au>Ciccarelli, Bryan T</au><au>Whitehead, Ian P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of vesicle transport and cell motility by Golgi-localized Dbs</atitle><jtitle>Small GTPases</jtitle><addtitle>Small GTPases</addtitle><date>2014-10-02</date><risdate>2014</risdate><volume>5</volume><issue>4</issue><spage>1</spage><epage>12</epage><pages>1-12</pages><issn>2154-1248</issn><eissn>2154-1256</eissn><abstract>DBS/MCF2L has been recently identified as a risk locus for osteoarthritis. It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms, a 130 kDa form (Dbs-130) that is localized to the Golgi complex, and an 80 kDa form (Dbs-80) that is localized to the endoplasmic reticulum (ER). We have previously described an inhibitor that binds to the RhoGEF domain of Dbs and blocks its transforming activity. Here we show that the inhibitor localizes to the Golgi, where it specifically interacts with Dbs-130. Inhibition of endogenous Dbs-130 activity is associated with reduced levels of activated Cdc42, enlarged Golgi, and resistance to Brefeldin A-mediated Golgi dispersal, suggesting a role for Dbs in vesicle transport. Cells treated with the inhibitor exhibit normal protein transport from the ER to the Golgi, but are defective in transport from the Golgi to the plasma membrane. Inhibition of Dbs-130 in MDA-MB-231 human breast tumor cells limits motility in both transwell and wound healing assays, but appears to have no effect on the organization of the microtubule cytoskeleton. The reduced motility is associated with a failure to reorient the Golgi toward the leading edge. This is consistent with the Golgi localization, and suggests that the Dbs-130 regulates aspects of the secretory pathway that are required to support cell polarization during directed migration.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>25483302</pmid><doi>10.4161/sgtp.28570</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biological Transport - drug effects breast cancer Brefeldin A - pharmacology Carrier Proteins - chemistry Carrier Proteins - metabolism cdc42 GTP-Binding Protein - metabolism Cell Line, Tumor cell motility Cell Movement - drug effects Cytoskeleton - metabolism Dbs Endoplasmic Reticulum - metabolism Golgi Apparatus - drug effects Golgi Apparatus - metabolism golgi complex guanine nucleotide exchange factor Guanine Nucleotide Exchange Factors - antagonists & inhibitors Guanine Nucleotide Exchange Factors - chemistry Guanine Nucleotide Exchange Factors - metabolism HeLa Cells Humans MCF2L osteoarthritis Protein Binding Protein Isoforms - antagonists & inhibitors Protein Isoforms - chemistry Protein Isoforms - metabolism Protein Structure, Tertiary Research Paper Rho RNA Interference RNA, Small Interfering - metabolism Secretory Vesicles - metabolism |
title | Regulation of vesicle transport and cell motility by Golgi-localized Dbs |
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