Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain
Ras-GRF is a guanine nucleotide exchange factor that activates Ras proteins. Its activity on Ras in cells is enhanced upon calcium influx. Activation follows calcium-induced binding of calmodulin to an IQ motif near the N-terminus of Ras-GRF. Ras-GRF also contains a Dbl homology (DH) domain C-termin...
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| Veröffentlicht in: | FEBS letters 1997-04, Vol.407 (1), p.111-115 |
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| creator | Freshney, Norman W. Goonesekera, Sunali D. Feig, Larry A. |
| description | Ras-GRF is a guanine nucleotide exchange factor that activates Ras proteins. Its activity on Ras in cells is enhanced upon calcium influx. Activation follows calcium-induced binding of calmodulin to an IQ motif near the N-terminus of Ras-GRF. Ras-GRF also contains a Dbl homology (DH) domain C-terminal to the IQ motif. In many proteins, DH domains act as exchange factors for Rho-GTPase family members. However, we failed to detect exchange activity of this domain on well characterized Rho family members. Instead, we found that mutations analogous to those that block exchange activity of Dbl prevented Ras-GRF activation by calcium/calmodulin in vivo. All DH domains are followed immediately by a pleckstrin homology (PH) domain. We found that a mutation at a conserved site within the PH domain following the DH domain also prevented Ras-GRF activation by calcium in vivo. These results suggest that in addition to playing a role as activators of Rho proteins, DH domains can also contribute to the coupling of cellular signals to Ras activation. |
| doi_str_mv | 10.1016/S0014-5793(97)00309-8 |
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Its activity on Ras in cells is enhanced upon calcium influx. Activation follows calcium-induced binding of calmodulin to an IQ motif near the N-terminus of Ras-GRF. Ras-GRF also contains a Dbl homology (DH) domain C-terminal to the IQ motif. In many proteins, DH domains act as exchange factors for Rho-GTPase family members. However, we failed to detect exchange activity of this domain on well characterized Rho family members. Instead, we found that mutations analogous to those that block exchange activity of Dbl prevented Ras-GRF activation by calcium/calmodulin in vivo. All DH domains are followed immediately by a pleckstrin homology (PH) domain. We found that a mutation at a conserved site within the PH domain following the DH domain also prevented Ras-GRF activation by calcium in vivo. These results suggest that in addition to playing a role as activators of Rho proteins, DH domains can also contribute to the coupling of cellular signals to Ras activation.</description><identifier>ISSN: 0014-5793</identifier><identifier>EISSN: 1873-3468</identifier><identifier>DOI: 10.1016/S0014-5793(97)00309-8</identifier><identifier>PMID: 9141492</identifier><language>eng</language><publisher>England: Elsevier B.V</publisher><subject>Calcium ; Calcium - metabolism ; Calmodulin ; Calmodulin - metabolism ; dbl homology ; Dbl homology domain ; ERK ; extracellular regulated kinase ; GAP ; GEF ; glutathione S-transferase ; GST ; GTP-Binding Proteins - metabolism ; GTPase ; GTPase activating protein ; guanine nucleotide exchange factor ; Guanine Nucleotide Exchange Factors ; Neuronal signaling ; pleckstrin homology ; Protein Binding ; Proteins - genetics ; Proteins - metabolism ; Proto-Oncogene Proteins ; Ras ; ras Guanine Nucleotide Exchange Factors ; ras Proteins - metabolism ; Ras-GRF ; ras-GRF1 ; Ras-guanine nucleotide releasing factor ; Sequence Homology, Amino Acid ; Signal Transduction ; son of sevenless ; SOS</subject><ispartof>FEBS letters, 1997-04, Vol.407 (1), p.111-115</ispartof><rights>1997 Federation of European Biochemical Societies</rights><rights>FEBS Letters 407 (1997) 1873-3468 © 2015 Federation of European Biochemical Societies</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5038-1c6985fe56957d52a342a0cdfabecd5fd80fb18d63c68db90851f07a1dd14923</citedby><cites>FETCH-LOGICAL-c5038-1c6985fe56957d52a342a0cdfabecd5fd80fb18d63c68db90851f07a1dd14923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2FS0014-5793%2897%2900309-8$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0014-5793(97)00309-8$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,1417,1433,3550,27924,27925,45574,45575,45995,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9141492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Freshney, Norman W.</creatorcontrib><creatorcontrib>Goonesekera, Sunali D.</creatorcontrib><creatorcontrib>Feig, Larry A.</creatorcontrib><title>Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain</title><title>FEBS letters</title><addtitle>FEBS Lett</addtitle><description>Ras-GRF is a guanine nucleotide exchange factor that activates Ras proteins. Its activity on Ras in cells is enhanced upon calcium influx. Activation follows calcium-induced binding of calmodulin to an IQ motif near the N-terminus of Ras-GRF. Ras-GRF also contains a Dbl homology (DH) domain C-terminal to the IQ motif. In many proteins, DH domains act as exchange factors for Rho-GTPase family members. However, we failed to detect exchange activity of this domain on well characterized Rho family members. Instead, we found that mutations analogous to those that block exchange activity of Dbl prevented Ras-GRF activation by calcium/calmodulin in vivo. All DH domains are followed immediately by a pleckstrin homology (PH) domain. We found that a mutation at a conserved site within the PH domain following the DH domain also prevented Ras-GRF activation by calcium in vivo. These results suggest that in addition to playing a role as activators of Rho proteins, DH domains can also contribute to the coupling of cellular signals to Ras activation.</description><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>Calmodulin</subject><subject>Calmodulin - metabolism</subject><subject>dbl homology</subject><subject>Dbl homology domain</subject><subject>ERK</subject><subject>extracellular regulated kinase</subject><subject>GAP</subject><subject>GEF</subject><subject>glutathione S-transferase</subject><subject>GST</subject><subject>GTP-Binding Proteins - metabolism</subject><subject>GTPase</subject><subject>GTPase activating protein</subject><subject>guanine nucleotide exchange factor</subject><subject>Guanine Nucleotide Exchange Factors</subject><subject>Neuronal signaling</subject><subject>pleckstrin homology</subject><subject>Protein Binding</subject><subject>Proteins - genetics</subject><subject>Proteins - metabolism</subject><subject>Proto-Oncogene Proteins</subject><subject>Ras</subject><subject>ras Guanine Nucleotide Exchange Factors</subject><subject>ras Proteins - metabolism</subject><subject>Ras-GRF</subject><subject>ras-GRF1</subject><subject>Ras-guanine nucleotide releasing factor</subject><subject>Sequence Homology, Amino Acid</subject><subject>Signal Transduction</subject><subject>son of sevenless</subject><subject>SOS</subject><issn>0014-5793</issn><issn>1873-3468</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFPJCEQhclG447u_gQTThv30ApDQ8Np46qjJiYm6m0PhIbCYdPdKHSr8-_tnpl41RMp3qtX8BVCh5QcU0LFyT0htCx4pdiRqn4Twogq5Dc0o7JiBSuF3EGzD8t3tJ_zfzLWkqo9tKdoSUs1n6F_p7YPL6YPscPR434JGN7s0nSPgL2xfUz4zuTi8m6B6xW2prFhaHGC5yEkyNh0OHT96MPndYOXsY1NfFxhF1sTuh9o15smw8_teYAeFhcPZ1fFze3l9dnpTWE5YbKgVijJPXCheOX43LByboh13tRgHfdOEl9T6QSzQrpaEcmpJ5Whzk1_YAfo1yb2KcXnAXKv25AtNI3pIA5ZV1IpLtjnRsqVFIJPRr4x2hRzTuD1UwqtSStNiZ7g6zV8PZHVqtJr-FqOfYfbAUPdgvvo2tIe9auN_hoaWH0tVC8u_s7XyiSoan09jfqziYIR7EuApLMN0Flw415sr10Mnzz2HSQxp50</recordid><startdate>19970421</startdate><enddate>19970421</enddate><creator>Freshney, Norman W.</creator><creator>Goonesekera, Sunali D.</creator><creator>Feig, Larry A.</creator><general>Elsevier B.V</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>7QP</scope><scope>7X8</scope></search><sort><creationdate>19970421</creationdate><title>Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain</title><author>Freshney, Norman W. ; Goonesekera, Sunali D. ; Feig, Larry A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5038-1c6985fe56957d52a342a0cdfabecd5fd80fb18d63c68db90851f07a1dd14923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Calcium</topic><topic>Calcium - metabolism</topic><topic>Calmodulin</topic><topic>Calmodulin - metabolism</topic><topic>dbl homology</topic><topic>Dbl homology domain</topic><topic>ERK</topic><topic>extracellular regulated kinase</topic><topic>GAP</topic><topic>GEF</topic><topic>glutathione S-transferase</topic><topic>GST</topic><topic>GTP-Binding Proteins - metabolism</topic><topic>GTPase</topic><topic>GTPase activating protein</topic><topic>guanine nucleotide exchange factor</topic><topic>Guanine Nucleotide Exchange Factors</topic><topic>Neuronal signaling</topic><topic>pleckstrin homology</topic><topic>Protein Binding</topic><topic>Proteins - genetics</topic><topic>Proteins - metabolism</topic><topic>Proto-Oncogene Proteins</topic><topic>Ras</topic><topic>ras Guanine Nucleotide Exchange Factors</topic><topic>ras Proteins - metabolism</topic><topic>Ras-GRF</topic><topic>ras-GRF1</topic><topic>Ras-guanine nucleotide releasing factor</topic><topic>Sequence Homology, Amino Acid</topic><topic>Signal Transduction</topic><topic>son of sevenless</topic><topic>SOS</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Freshney, Norman W.</creatorcontrib><creatorcontrib>Goonesekera, Sunali D.</creatorcontrib><creatorcontrib>Feig, Larry A.</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>Calcium & Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>FEBS letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Freshney, Norman W.</au><au>Goonesekera, Sunali D.</au><au>Feig, Larry A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain</atitle><jtitle>FEBS letters</jtitle><addtitle>FEBS Lett</addtitle><date>1997-04-21</date><risdate>1997</risdate><volume>407</volume><issue>1</issue><spage>111</spage><epage>115</epage><pages>111-115</pages><issn>0014-5793</issn><eissn>1873-3468</eissn><abstract>Ras-GRF is a guanine nucleotide exchange factor that activates Ras proteins. Its activity on Ras in cells is enhanced upon calcium influx. Activation follows calcium-induced binding of calmodulin to an IQ motif near the N-terminus of Ras-GRF. Ras-GRF also contains a Dbl homology (DH) domain C-terminal to the IQ motif. In many proteins, DH domains act as exchange factors for Rho-GTPase family members. However, we failed to detect exchange activity of this domain on well characterized Rho family members. Instead, we found that mutations analogous to those that block exchange activity of Dbl prevented Ras-GRF activation by calcium/calmodulin in vivo. All DH domains are followed immediately by a pleckstrin homology (PH) domain. We found that a mutation at a conserved site within the PH domain following the DH domain also prevented Ras-GRF activation by calcium in vivo. These results suggest that in addition to playing a role as activators of Rho proteins, DH domains can also contribute to the coupling of cellular signals to Ras activation.</abstract><cop>England</cop><pub>Elsevier B.V</pub><pmid>9141492</pmid><doi>10.1016/S0014-5793(97)00309-8</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Calcium Calcium - metabolism Calmodulin Calmodulin - metabolism dbl homology Dbl homology domain ERK extracellular regulated kinase GAP GEF glutathione S-transferase GST GTP-Binding Proteins - metabolism GTPase GTPase activating protein guanine nucleotide exchange factor Guanine Nucleotide Exchange Factors Neuronal signaling pleckstrin homology Protein Binding Proteins - genetics Proteins - metabolism Proto-Oncogene Proteins Ras ras Guanine Nucleotide Exchange Factors ras Proteins - metabolism Ras-GRF ras-GRF1 Ras-guanine nucleotide releasing factor Sequence Homology, Amino Acid Signal Transduction son of sevenless SOS |
| title | Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain |
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