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Functional Interactions of Raf and MEK with Jun-N-Terminal Kinase (JNK) Result in a Positive Feedback Loop on the Oncogenic Ras Signaling Pathway
In previous studies we have found that oncogenic (Val 12)-ras-p21 induces Xenopus laevis oocyte maturation that is selectively blocked by two ras-p21 peptides, 35−47, also called PNC-7, that blocks its interaction with raf, and 96−110, also called PNC-2, that blocks its interaction with jun-N-termin...
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| Published in: | Biochemistry (Easton) 2005-08, Vol.44 (32), p.10784-10795 |
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| creator | Adler, Victor Qu, Yongxia Smith, Steven J Izotova, Lara Pestka, Sidney Kung, Hsiang-Fu Lin, Marie Friedman, Fred K Chie, Lyndon Chung, Denise Boutjdir, Mohamed Pincus, Matthew R |
| description | In previous studies we have found that oncogenic (Val 12)-ras-p21 induces Xenopus laevis oocyte maturation that is selectively blocked by two ras-p21 peptides, 35−47, also called PNC-7, that blocks its interaction with raf, and 96−110, also called PNC-2, that blocks its interaction with jun-N-terminal kinase (JNK). Each peptide blocks activation of both JNK and MAP kinase (MAPK or ERK) suggesting interaction between the raf−MEK−ERK and JNK−jun pathways. We further found that dominant negative raf blocks JNK induction of oocyte maturation, again suggesting cross-talk between pathways. In this study, we have undertaken to determine where these points of cross-talk occur. First, we have immunoprecipitated injected Val 12-Ha-ras-p21 from oocytes and found that a complex forms between ras-p21 raf, MEK, MAPK, and JNK. Co-injection of either peptide, but not a control peptide, causes diminished binding of ras-p21, raf, and JNK. Thus, one site of interaction is cooperative binding of Val 12-ras-p21 to raf and JNK. Second, we have injected JNK, c-raf, and MEK into oocytes alone and in the presence of raf and MEK inhibitors and found that JNK activation is independent of the raf−MEK−MAPK pathway but that activated JNK activates raf, allowing for activation of ERK. Furthermore, we have found that constitutively activated MEK activates JNK. We have corroborated these findings in studies with isolated protein components from a human astrocyte (U-251) cell line; that is, JNK phosphorylates raf but not the reverse; MEK phosphorylates JNK but not the reverse. We further have found that JNK does not phosphorylate MAPK and that MAPK does not phosphorylate JNK. The stress-inducing agent, anisomycin, causes activation of JNK, raf, MEK, and ERK in this cell line; activation of JNK is not inhibitable by the MEK inhibitor, U0126, while activation of raf, MEK, and ERK are blocked by this agent. These results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop. |
| doi_str_mv | 10.1021/bi050619j |
| format | article |
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Each peptide blocks activation of both JNK and MAP kinase (MAPK or ERK) suggesting interaction between the raf−MEK−ERK and JNK−jun pathways. We further found that dominant negative raf blocks JNK induction of oocyte maturation, again suggesting cross-talk between pathways. In this study, we have undertaken to determine where these points of cross-talk occur. First, we have immunoprecipitated injected Val 12-Ha-ras-p21 from oocytes and found that a complex forms between ras-p21 raf, MEK, MAPK, and JNK. Co-injection of either peptide, but not a control peptide, causes diminished binding of ras-p21, raf, and JNK. Thus, one site of interaction is cooperative binding of Val 12-ras-p21 to raf and JNK. Second, we have injected JNK, c-raf, and MEK into oocytes alone and in the presence of raf and MEK inhibitors and found that JNK activation is independent of the raf−MEK−MAPK pathway but that activated JNK activates raf, allowing for activation of ERK. Furthermore, we have found that constitutively activated MEK activates JNK. We have corroborated these findings in studies with isolated protein components from a human astrocyte (U-251) cell line; that is, JNK phosphorylates raf but not the reverse; MEK phosphorylates JNK but not the reverse. We further have found that JNK does not phosphorylate MAPK and that MAPK does not phosphorylate JNK. The stress-inducing agent, anisomycin, causes activation of JNK, raf, MEK, and ERK in this cell line; activation of JNK is not inhibitable by the MEK inhibitor, U0126, while activation of raf, MEK, and ERK are blocked by this agent. These results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi050619j</identifier><identifier>PMID: 16086581</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Butadienes - pharmacology ; Cell Line, Tumor ; Feedback, Physiological ; Humans ; JNK Mitogen-Activated Protein Kinases - metabolism ; MAP Kinase Kinase 1 - antagonists & inhibitors ; MAP Kinase Kinase 1 - metabolism ; Multiprotein Complexes ; Nitriles - pharmacology ; Oocytes ; Phosphorylation ; Proto-Oncogene Proteins c-raf - metabolism ; Proto-Oncogene Proteins p21(ras) - metabolism ; Receptor Cross-Talk ; Signal Transduction ; Xenopus laevis</subject><ispartof>Biochemistry (Easton), 2005-08, Vol.44 (32), p.10784-10795</ispartof><rights>Copyright © 2005 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a351t-61a1e60cccdbf7207c2075d8f4b6e722bfee15c2a76c71b4071d96a1af6e66e83</citedby><cites>FETCH-LOGICAL-a351t-61a1e60cccdbf7207c2075d8f4b6e722bfee15c2a76c71b4071d96a1af6e66e83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,783,787,27936,27937</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16086581$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adler, Victor</creatorcontrib><creatorcontrib>Qu, Yongxia</creatorcontrib><creatorcontrib>Smith, Steven J</creatorcontrib><creatorcontrib>Izotova, Lara</creatorcontrib><creatorcontrib>Pestka, Sidney</creatorcontrib><creatorcontrib>Kung, Hsiang-Fu</creatorcontrib><creatorcontrib>Lin, Marie</creatorcontrib><creatorcontrib>Friedman, Fred K</creatorcontrib><creatorcontrib>Chie, Lyndon</creatorcontrib><creatorcontrib>Chung, Denise</creatorcontrib><creatorcontrib>Boutjdir, Mohamed</creatorcontrib><creatorcontrib>Pincus, Matthew R</creatorcontrib><title>Functional Interactions of Raf and MEK with Jun-N-Terminal Kinase (JNK) Result in a Positive Feedback Loop on the Oncogenic Ras Signaling Pathway</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>In previous studies we have found that oncogenic (Val 12)-ras-p21 induces Xenopus laevis oocyte maturation that is selectively blocked by two ras-p21 peptides, 35−47, also called PNC-7, that blocks its interaction with raf, and 96−110, also called PNC-2, that blocks its interaction with jun-N-terminal kinase (JNK). Each peptide blocks activation of both JNK and MAP kinase (MAPK or ERK) suggesting interaction between the raf−MEK−ERK and JNK−jun pathways. We further found that dominant negative raf blocks JNK induction of oocyte maturation, again suggesting cross-talk between pathways. In this study, we have undertaken to determine where these points of cross-talk occur. First, we have immunoprecipitated injected Val 12-Ha-ras-p21 from oocytes and found that a complex forms between ras-p21 raf, MEK, MAPK, and JNK. Co-injection of either peptide, but not a control peptide, causes diminished binding of ras-p21, raf, and JNK. Thus, one site of interaction is cooperative binding of Val 12-ras-p21 to raf and JNK. Second, we have injected JNK, c-raf, and MEK into oocytes alone and in the presence of raf and MEK inhibitors and found that JNK activation is independent of the raf−MEK−MAPK pathway but that activated JNK activates raf, allowing for activation of ERK. Furthermore, we have found that constitutively activated MEK activates JNK. We have corroborated these findings in studies with isolated protein components from a human astrocyte (U-251) cell line; that is, JNK phosphorylates raf but not the reverse; MEK phosphorylates JNK but not the reverse. We further have found that JNK does not phosphorylate MAPK and that MAPK does not phosphorylate JNK. The stress-inducing agent, anisomycin, causes activation of JNK, raf, MEK, and ERK in this cell line; activation of JNK is not inhibitable by the MEK inhibitor, U0126, while activation of raf, MEK, and ERK are blocked by this agent. These results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop.</description><subject>Animals</subject><subject>Butadienes - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Feedback, Physiological</subject><subject>Humans</subject><subject>JNK Mitogen-Activated Protein Kinases - metabolism</subject><subject>MAP Kinase Kinase 1 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 1 - metabolism</subject><subject>Multiprotein Complexes</subject><subject>Nitriles - pharmacology</subject><subject>Oocytes</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-raf - metabolism</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>Receptor Cross-Talk</subject><subject>Signal Transduction</subject><subject>Xenopus laevis</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNptkMFOGzEQhq2qVUmBQ1-gmkurcthib9be3SNChELSEEEquFle72zisLHTtRfKY_SNa5qIXjjMjEbz6f81PyEfGf3GaMqOK0M5FaxcvSEDxlOaZGXJ35IBpVQkaSnoHvng_SquGc2z92SPCVoIXrAB-TPqrQ7GWdXChQ3YqX-bB9fAtWpA2Rp-nI3h0YQlXPY2mSZz7NbmmR_H7hG-Xk7HR3CNvm8DGAsKZs6bYB4QRoh1pfQ9TJzbgLMQlghXVrsFWqOjgYcbs4haxi5gpsLyUT0dkHeNaj0e7uY--Tk6m59-TyZX5xenJ5NEDTkLiWCKoaBa67pq8pTmOhaviyarBOZpWjWIjOtU5ULnrIqPs7oUiqlGoBBYDPfJl63upnO_evRBro3X2LbKouu9FEUmaC5EBI-2oO6c9x02ctOZteqeJKPyOX_5kn9kP-1E-2qN9X9yF3gEki1gfMDfL3fV3UuRD3Mu57Mbyco7Pr27HcvbyH_e8kp7uXJ9F8Pyrxj_Bf3Pm3c</recordid><startdate>20050816</startdate><enddate>20050816</enddate><creator>Adler, Victor</creator><creator>Qu, Yongxia</creator><creator>Smith, Steven J</creator><creator>Izotova, Lara</creator><creator>Pestka, Sidney</creator><creator>Kung, Hsiang-Fu</creator><creator>Lin, Marie</creator><creator>Friedman, Fred K</creator><creator>Chie, Lyndon</creator><creator>Chung, Denise</creator><creator>Boutjdir, Mohamed</creator><creator>Pincus, Matthew R</creator><general>American Chemical Society</general><scope>BSCLL</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>20050816</creationdate><title>Functional Interactions of Raf and MEK with Jun-N-Terminal Kinase (JNK) Result in a Positive Feedback Loop on the Oncogenic Ras Signaling Pathway</title><author>Adler, Victor ; Qu, Yongxia ; Smith, Steven J ; Izotova, Lara ; Pestka, Sidney ; Kung, Hsiang-Fu ; Lin, Marie ; Friedman, Fred K ; Chie, Lyndon ; Chung, Denise ; Boutjdir, Mohamed ; Pincus, Matthew R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a351t-61a1e60cccdbf7207c2075d8f4b6e722bfee15c2a76c71b4071d96a1af6e66e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Butadienes - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Feedback, Physiological</topic><topic>Humans</topic><topic>JNK Mitogen-Activated Protein Kinases - metabolism</topic><topic>MAP Kinase Kinase 1 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 1 - metabolism</topic><topic>Multiprotein Complexes</topic><topic>Nitriles - pharmacology</topic><topic>Oocytes</topic><topic>Phosphorylation</topic><topic>Proto-Oncogene Proteins c-raf - metabolism</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>Receptor Cross-Talk</topic><topic>Signal Transduction</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adler, Victor</creatorcontrib><creatorcontrib>Qu, Yongxia</creatorcontrib><creatorcontrib>Smith, Steven J</creatorcontrib><creatorcontrib>Izotova, Lara</creatorcontrib><creatorcontrib>Pestka, Sidney</creatorcontrib><creatorcontrib>Kung, Hsiang-Fu</creatorcontrib><creatorcontrib>Lin, Marie</creatorcontrib><creatorcontrib>Friedman, Fred K</creatorcontrib><creatorcontrib>Chie, Lyndon</creatorcontrib><creatorcontrib>Chung, Denise</creatorcontrib><creatorcontrib>Boutjdir, Mohamed</creatorcontrib><creatorcontrib>Pincus, Matthew R</creatorcontrib><collection>Istex</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>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Adler, Victor</au><au>Qu, Yongxia</au><au>Smith, Steven J</au><au>Izotova, Lara</au><au>Pestka, Sidney</au><au>Kung, Hsiang-Fu</au><au>Lin, Marie</au><au>Friedman, Fred K</au><au>Chie, Lyndon</au><au>Chung, Denise</au><au>Boutjdir, Mohamed</au><au>Pincus, Matthew R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functional Interactions of Raf and MEK with Jun-N-Terminal Kinase (JNK) Result in a Positive Feedback Loop on the Oncogenic Ras Signaling Pathway</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2005-08-16</date><risdate>2005</risdate><volume>44</volume><issue>32</issue><spage>10784</spage><epage>10795</epage><pages>10784-10795</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>In previous studies we have found that oncogenic (Val 12)-ras-p21 induces Xenopus laevis oocyte maturation that is selectively blocked by two ras-p21 peptides, 35−47, also called PNC-7, that blocks its interaction with raf, and 96−110, also called PNC-2, that blocks its interaction with jun-N-terminal kinase (JNK). Each peptide blocks activation of both JNK and MAP kinase (MAPK or ERK) suggesting interaction between the raf−MEK−ERK and JNK−jun pathways. We further found that dominant negative raf blocks JNK induction of oocyte maturation, again suggesting cross-talk between pathways. In this study, we have undertaken to determine where these points of cross-talk occur. First, we have immunoprecipitated injected Val 12-Ha-ras-p21 from oocytes and found that a complex forms between ras-p21 raf, MEK, MAPK, and JNK. Co-injection of either peptide, but not a control peptide, causes diminished binding of ras-p21, raf, and JNK. Thus, one site of interaction is cooperative binding of Val 12-ras-p21 to raf and JNK. Second, we have injected JNK, c-raf, and MEK into oocytes alone and in the presence of raf and MEK inhibitors and found that JNK activation is independent of the raf−MEK−MAPK pathway but that activated JNK activates raf, allowing for activation of ERK. Furthermore, we have found that constitutively activated MEK activates JNK. We have corroborated these findings in studies with isolated protein components from a human astrocyte (U-251) cell line; that is, JNK phosphorylates raf but not the reverse; MEK phosphorylates JNK but not the reverse. We further have found that JNK does not phosphorylate MAPK and that MAPK does not phosphorylate JNK. The stress-inducing agent, anisomycin, causes activation of JNK, raf, MEK, and ERK in this cell line; activation of JNK is not inhibitable by the MEK inhibitor, U0126, while activation of raf, MEK, and ERK are blocked by this agent. These results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>16086581</pmid><doi>10.1021/bi050619j</doi><tpages>12</tpages></addata></record> |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Butadienes - pharmacology Cell Line, Tumor Feedback, Physiological Humans JNK Mitogen-Activated Protein Kinases - metabolism MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 1 - metabolism Multiprotein Complexes Nitriles - pharmacology Oocytes Phosphorylation Proto-Oncogene Proteins c-raf - metabolism Proto-Oncogene Proteins p21(ras) - metabolism Receptor Cross-Talk Signal Transduction Xenopus laevis |
| title | Functional Interactions of Raf and MEK with Jun-N-Terminal Kinase (JNK) Result in a Positive Feedback Loop on the Oncogenic Ras Signaling Pathway |
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