Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner
Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-relat...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-08, Vol.278 (35), p.32493-32496 |
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| container_title | The Journal of biological chemistry |
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| creator | Castro, Ariel F. Rebhun, John F. Clark, Geoffrey J. Quilliam, Lawrence A. |
| description | Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug. |
| doi_str_mv | 10.1074/jbc.C300226200 |
| format | Article |
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Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.C300226200</identifier><identifier>PMID: 12842888</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antineoplastic Agents - pharmacology ; Cell Line ; Enzyme Activation ; Gene Expression Regulation, Enzymologic ; Humans ; Immunoblotting ; Monomeric GTP-Binding Proteins - metabolism ; Neuropeptides - metabolism ; Phosphorylation ; Plasmids - metabolism ; Protein Binding ; Protein Kinases - metabolism ; Protein Prenylation ; Ras Homolog Enriched in Brain Protein ; Repressor Proteins - metabolism ; Ribosomal Protein S6 Kinases - metabolism ; Sirolimus - pharmacology ; TOR Serine-Threonine Kinases ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins</subject><ispartof>The Journal of biological chemistry, 2003-08, Vol.278 (35), p.32493-32496</ispartof><rights>2003 © 2003 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-99474507d5920576331ec28aea114d33001a6b6cdd99115c2bff0fce291e6c4f3</citedby><cites>FETCH-LOGICAL-c475t-99474507d5920576331ec28aea114d33001a6b6cdd99115c2bff0fce291e6c4f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12842888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Castro, Ariel F.</creatorcontrib><creatorcontrib>Rebhun, John F.</creatorcontrib><creatorcontrib>Clark, Geoffrey J.</creatorcontrib><creatorcontrib>Quilliam, Lawrence A.</creatorcontrib><title>Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line</subject><subject>Enzyme Activation</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Monomeric GTP-Binding Proteins - metabolism</subject><subject>Neuropeptides - metabolism</subject><subject>Phosphorylation</subject><subject>Plasmids - metabolism</subject><subject>Protein Binding</subject><subject>Protein Kinases - metabolism</subject><subject>Protein Prenylation</subject><subject>Ras Homolog Enriched in Brain Protein</subject><subject>Repressor Proteins - metabolism</subject><subject>Ribosomal Protein S6 Kinases - metabolism</subject><subject>Sirolimus - pharmacology</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Tuberous Sclerosis Complex 2 Protein</subject><subject>Tumor Suppressor Proteins</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1v1DAURS0EokNhyxJ5gRAsMvgzsZclooAoArWDxM5y7BfGVeKkdqYwa_44pjNSV3hjyzr36r2D0HNK1pQ04u1159YtJ4SxmhHyAK0oUbzikv54iFblm1aaSXWCnuR8TcoRmj5GJ5QpwZRSK_Tncgsdfheiz3iz6yBNu4yv3FAeOWTcTuM8wG_M8OvNVcveYBs9_pamcVqgcDX-HKLNgM_cEm7tEqaIQ8QWX9rZjnsXYnWXOLcpQt4Pd0TlYYboIS74i40R0lP0qLdDhmfH-xR9P3-_aT9WF18_fGrPLionGrlUWotGSNJ4qRmRTc05BceUBUup8LxIoLbuaue91pRKx7q-J70DpinUTvT8FL069M5putlBXswYsoNhsBHK2qbhUnHBSQHXB9AVCzlBb-YURpv2hhLzT7sp2s299hJ4cWzedSP4e_zouQAvD8A2_Nz-CglMFya3hdGwRhkuDWdC84KpAwZFw22AZLILEB34EnGL8VP43wh_ASXVm6w</recordid><startdate>20030829</startdate><enddate>20030829</enddate><creator>Castro, Ariel F.</creator><creator>Rebhun, John F.</creator><creator>Clark, Geoffrey J.</creator><creator>Quilliam, Lawrence A.</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></search><sort><creationdate>20030829</creationdate><title>Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner</title><author>Castro, Ariel F. ; Rebhun, John F. ; Clark, Geoffrey J. ; Quilliam, Lawrence A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-99474507d5920576331ec28aea114d33001a6b6cdd99115c2bff0fce291e6c4f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line</topic><topic>Enzyme Activation</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Monomeric GTP-Binding Proteins - metabolism</topic><topic>Neuropeptides - metabolism</topic><topic>Phosphorylation</topic><topic>Plasmids - metabolism</topic><topic>Protein Binding</topic><topic>Protein Kinases - metabolism</topic><topic>Protein Prenylation</topic><topic>Ras Homolog Enriched in Brain Protein</topic><topic>Repressor Proteins - metabolism</topic><topic>Ribosomal Protein S6 Kinases - metabolism</topic><topic>Sirolimus - pharmacology</topic><topic>TOR Serine-Threonine Kinases</topic><topic>Tuberous Sclerosis Complex 2 Protein</topic><topic>Tumor Suppressor Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Castro, Ariel F.</creatorcontrib><creatorcontrib>Rebhun, John F.</creatorcontrib><creatorcontrib>Clark, Geoffrey J.</creatorcontrib><creatorcontrib>Quilliam, Lawrence 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>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Castro, Ariel F.</au><au>Rebhun, John F.</au><au>Clark, Geoffrey J.</au><au>Quilliam, Lawrence A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-08-29</date><risdate>2003</risdate><volume>278</volume><issue>35</issue><spage>32493</spage><epage>32496</epage><pages>32493-32496</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. 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| ispartof | The Journal of biological chemistry, 2003-08, Vol.278 (35), p.32493-32496 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Antineoplastic Agents - pharmacology Cell Line Enzyme Activation Gene Expression Regulation, Enzymologic Humans Immunoblotting Monomeric GTP-Binding Proteins - metabolism Neuropeptides - metabolism Phosphorylation Plasmids - metabolism Protein Binding Protein Kinases - metabolism Protein Prenylation Ras Homolog Enriched in Brain Protein Repressor Proteins - metabolism Ribosomal Protein S6 Kinases - metabolism Sirolimus - pharmacology TOR Serine-Threonine Kinases Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins |
| title | Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner |
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