Role of MLK3-mediated Activation of p70 S6 Kinase in Rac1 Transformation
The signaling pathways that mediate the transforming activity of the Rac1 GTPase remain to be determined. In the present study, we used effector domain mutants of the constitutively activated Rac(61L) mutant that display differential transforming activities and differential activation of downstream...
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| Veröffentlicht in: | The Journal of biological chemistry 2002-02, Vol.277 (7), p.4770-4777 |
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| container_title | The Journal of biological chemistry |
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| creator | Lambert, John M Karnoub, Antoine E Graves, Lee M Campbell, Sharon L Der, Channing J |
| description | The signaling pathways that mediate the transforming activity of the Rac1 GTPase remain to be determined. In the present study,
we used effector domain mutants of the constitutively activated Rac(61L) mutant that display differential transforming activities
and differential activation of downstream effector pathways to investigate the contribution of p70 S6 kinase (p70 S6K ) to Rac1 transformation and to decipher the signaling pathways leading from Rac1 to p70 S6K . First, we found that Rac1 transforming activity could be dissociated from Rac1 activation of p70 S6K . A weakly transforming Rac1 mutant retained the ability to activate p70 S6K , whereas some potently transforming effector mutants were impaired in their ability to activate p70 S6K . These data suggest that p70 S6K is not necessary to promote full Rac1 transforming activity. We also found a strong correlation between the ability of the
Rac(61L) effector mutants to activate p70 S6K and their ability to activate the JNK mitogen-activated protein kinase. We found that the MLK3 serine/threonine kinase activated
JNK and p70 S6K , whereas activation of p70 S6K by Rac(61L) was significantly inhibited by dominant-negative MLK3. Additionally, the ability of the Rac(61L) effector mutants
to activate MLK3 correlated well with their ability to activate p70 S6K and JNK. Taken together, these results provide evidence that Rac1 coordinately activates p70 S6K and JNK via MLK3 activation. Finally, we found that co-expression of wild type, but not kinase-dead, MLK3 significantly inhibited
Rac1 transforming activity. These results suggest that MLK3 may be a negative regulator of the growth-promoting and transforming
properties of Rac1. |
| doi_str_mv | 10.1074/jbc.M109379200 |
| format | Article |
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we used effector domain mutants of the constitutively activated Rac(61L) mutant that display differential transforming activities
and differential activation of downstream effector pathways to investigate the contribution of p70 S6 kinase (p70 S6K ) to Rac1 transformation and to decipher the signaling pathways leading from Rac1 to p70 S6K . First, we found that Rac1 transforming activity could be dissociated from Rac1 activation of p70 S6K . A weakly transforming Rac1 mutant retained the ability to activate p70 S6K , whereas some potently transforming effector mutants were impaired in their ability to activate p70 S6K . These data suggest that p70 S6K is not necessary to promote full Rac1 transforming activity. We also found a strong correlation between the ability of the
Rac(61L) effector mutants to activate p70 S6K and their ability to activate the JNK mitogen-activated protein kinase. We found that the MLK3 serine/threonine kinase activated
JNK and p70 S6K , whereas activation of p70 S6K by Rac(61L) was significantly inhibited by dominant-negative MLK3. Additionally, the ability of the Rac(61L) effector mutants
to activate MLK3 correlated well with their ability to activate p70 S6K and JNK. Taken together, these results provide evidence that Rac1 coordinately activates p70 S6K and JNK via MLK3 activation. Finally, we found that co-expression of wild type, but not kinase-dead, MLK3 significantly inhibited
Rac1 transforming activity. These results suggest that MLK3 may be a negative regulator of the growth-promoting and transforming
properties of Rac1.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M109379200</identifier><identifier>PMID: 11713255</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>3T3 Cells ; Agar - pharmacology ; Animals ; Blotting, Western ; Cell Line ; Enzyme Activation ; Genes, Reporter ; Genetic Vectors ; Humans ; Luciferases - metabolism ; MAP Kinase Kinase Kinases - metabolism ; MAP Kinase Kinase Kinases - physiology ; Mice ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; Mitogen-Activated Protein Kinases - metabolism ; Mutation ; Plasmids - metabolism ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; rac1 GTP-Binding Protein - metabolism ; Ribosomal Protein S6 Kinases - metabolism ; Signal Transduction ; Transfection</subject><ispartof>The Journal of biological chemistry, 2002-02, Vol.277 (7), p.4770-4777</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-1812eda05b22b3ae99e8507184756f53aec157980e8569bff15cbf10961a26bb3</citedby><cites>FETCH-LOGICAL-c469t-1812eda05b22b3ae99e8507184756f53aec157980e8569bff15cbf10961a26bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11713255$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lambert, John M</creatorcontrib><creatorcontrib>Karnoub, Antoine E</creatorcontrib><creatorcontrib>Graves, Lee M</creatorcontrib><creatorcontrib>Campbell, Sharon L</creatorcontrib><creatorcontrib>Der, Channing J</creatorcontrib><title>Role of MLK3-mediated Activation of p70 S6 Kinase in Rac1 Transformation</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The signaling pathways that mediate the transforming activity of the Rac1 GTPase remain to be determined. In the present study,
we used effector domain mutants of the constitutively activated Rac(61L) mutant that display differential transforming activities
and differential activation of downstream effector pathways to investigate the contribution of p70 S6 kinase (p70 S6K ) to Rac1 transformation and to decipher the signaling pathways leading from Rac1 to p70 S6K . First, we found that Rac1 transforming activity could be dissociated from Rac1 activation of p70 S6K . A weakly transforming Rac1 mutant retained the ability to activate p70 S6K , whereas some potently transforming effector mutants were impaired in their ability to activate p70 S6K . These data suggest that p70 S6K is not necessary to promote full Rac1 transforming activity. We also found a strong correlation between the ability of the
Rac(61L) effector mutants to activate p70 S6K and their ability to activate the JNK mitogen-activated protein kinase. We found that the MLK3 serine/threonine kinase activated
JNK and p70 S6K , whereas activation of p70 S6K by Rac(61L) was significantly inhibited by dominant-negative MLK3. Additionally, the ability of the Rac(61L) effector mutants
to activate MLK3 correlated well with their ability to activate p70 S6K and JNK. Taken together, these results provide evidence that Rac1 coordinately activates p70 S6K and JNK via MLK3 activation. Finally, we found that co-expression of wild type, but not kinase-dead, MLK3 significantly inhibited
Rac1 transforming activity. These results suggest that MLK3 may be a negative regulator of the growth-promoting and transforming
properties of Rac1.</description><subject>3T3 Cells</subject><subject>Agar - pharmacology</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Enzyme Activation</subject><subject>Genes, Reporter</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Luciferases - metabolism</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>MAP Kinase Kinase Kinases - physiology</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 8</subject><subject>Mitogen-Activated Protein Kinase Kinase Kinase 11</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Mutation</subject><subject>Plasmids - metabolism</subject><subject>Precipitin Tests</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>Ribosomal Protein S6 Kinases - metabolism</subject><subject>Signal Transduction</subject><subject>Transfection</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1LAzEQhoMotlavHmXx4G1rJtlsNsciaqUtQq3gLSRp1qbsR022iv_e1BY6l4F3nhmYB6FrwEPAPLtfazOcARaUC4LxCeoDLmhKGXycoj7GBFJBWNFDFyGscaxMwDnqAXCghLE-Gs_byiZtmcymE5rWdulUZ5fJyHTuW3WubXazDcfJW55MXKOCTVyTzJWBZOFVE8rW1__cJTorVRXs1aEP0PvT4-JhnE5fn18eRtPUZLnoUiiA2KXCTBOiqbJC2IJhDkXGWV6ymBhgXBQ4xrnQZQnM6DI-mIMiudZ0gO72dze-_dra0MnaBWOrSjW23QbJIcsYz7MIDveg8W0I3pZy412t_K8ELHfuZHQnj-7iws3h8lZHEUf8ICsCt3tg5T5XP85bqV1rVraWhHPJZcY5pn87hnLj</recordid><startdate>20020215</startdate><enddate>20020215</enddate><creator>Lambert, John M</creator><creator>Karnoub, Antoine E</creator><creator>Graves, Lee M</creator><creator>Campbell, Sharon L</creator><creator>Der, Channing J</creator><general>American Society for Biochemistry and Molecular Biology</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></search><sort><creationdate>20020215</creationdate><title>Role of MLK3-mediated Activation of p70 S6 Kinase in Rac1 Transformation</title><author>Lambert, John M ; Karnoub, Antoine E ; Graves, Lee M ; Campbell, Sharon L ; Der, Channing J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-1812eda05b22b3ae99e8507184756f53aec157980e8569bff15cbf10961a26bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>3T3 Cells</topic><topic>Agar - pharmacology</topic><topic>Animals</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Enzyme Activation</topic><topic>Genes, Reporter</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Luciferases - metabolism</topic><topic>MAP Kinase Kinase Kinases - metabolism</topic><topic>MAP Kinase Kinase Kinases - physiology</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 8</topic><topic>Mitogen-Activated Protein Kinase Kinase Kinase 11</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Mutation</topic><topic>Plasmids - metabolism</topic><topic>Precipitin Tests</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>Ribosomal Protein S6 Kinases - metabolism</topic><topic>Signal Transduction</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lambert, John M</creatorcontrib><creatorcontrib>Karnoub, Antoine E</creatorcontrib><creatorcontrib>Graves, Lee M</creatorcontrib><creatorcontrib>Campbell, Sharon L</creatorcontrib><creatorcontrib>Der, Channing J</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><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lambert, John M</au><au>Karnoub, Antoine E</au><au>Graves, Lee M</au><au>Campbell, Sharon L</au><au>Der, Channing J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of MLK3-mediated Activation of p70 S6 Kinase in Rac1 Transformation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-02-15</date><risdate>2002</risdate><volume>277</volume><issue>7</issue><spage>4770</spage><epage>4777</epage><pages>4770-4777</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The signaling pathways that mediate the transforming activity of the Rac1 GTPase remain to be determined. In the present study,
we used effector domain mutants of the constitutively activated Rac(61L) mutant that display differential transforming activities
and differential activation of downstream effector pathways to investigate the contribution of p70 S6 kinase (p70 S6K ) to Rac1 transformation and to decipher the signaling pathways leading from Rac1 to p70 S6K . First, we found that Rac1 transforming activity could be dissociated from Rac1 activation of p70 S6K . A weakly transforming Rac1 mutant retained the ability to activate p70 S6K , whereas some potently transforming effector mutants were impaired in their ability to activate p70 S6K . These data suggest that p70 S6K is not necessary to promote full Rac1 transforming activity. We also found a strong correlation between the ability of the
Rac(61L) effector mutants to activate p70 S6K and their ability to activate the JNK mitogen-activated protein kinase. We found that the MLK3 serine/threonine kinase activated
JNK and p70 S6K , whereas activation of p70 S6K by Rac(61L) was significantly inhibited by dominant-negative MLK3. Additionally, the ability of the Rac(61L) effector mutants
to activate MLK3 correlated well with their ability to activate p70 S6K and JNK. Taken together, these results provide evidence that Rac1 coordinately activates p70 S6K and JNK via MLK3 activation. Finally, we found that co-expression of wild type, but not kinase-dead, MLK3 significantly inhibited
Rac1 transforming activity. These results suggest that MLK3 may be a negative regulator of the growth-promoting and transforming
properties of Rac1.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>11713255</pmid><doi>10.1074/jbc.M109379200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | 3T3 Cells Agar - pharmacology Animals Blotting, Western Cell Line Enzyme Activation Genes, Reporter Genetic Vectors Humans Luciferases - metabolism MAP Kinase Kinase Kinases - metabolism MAP Kinase Kinase Kinases - physiology Mice Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinase Kinase Kinase 11 Mitogen-Activated Protein Kinases - metabolism Mutation Plasmids - metabolism Precipitin Tests Protein Binding Protein Structure, Tertiary rac1 GTP-Binding Protein - metabolism Ribosomal Protein S6 Kinases - metabolism Signal Transduction Transfection |
| title | Role of MLK3-mediated Activation of p70 S6 Kinase in Rac1 Transformation |
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