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Article: Functional interactions of raf and MEK with Jun-N-terminal kinase (JNK) result in a positive feedback loop on the oncogenic ras signaling pathway

TitleFunctional interactions of raf and MEK with Jun-N-terminal kinase (JNK) result in a positive feedback loop on the oncogenic ras signaling pathway
Authors
Issue Date2005
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2005, v. 44 n. 32, p. 10784-10795 How to Cite?
AbstractIn 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. © 2005 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/87993
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorAdler, Ven_HK
dc.contributor.authorQu, Yen_HK
dc.contributor.authorSmith, SJen_HK
dc.contributor.authorIzotova, Len_HK
dc.contributor.authorPestka, Sen_HK
dc.contributor.authorKung, HFen_HK
dc.contributor.authorLin, Men_HK
dc.contributor.authorFriedman, FKen_HK
dc.contributor.authorChie, Len_HK
dc.contributor.authorChung, Den_HK
dc.contributor.authorBoutjdir, Men_HK
dc.contributor.authorPincus, MRen_HK
dc.date.accessioned2010-09-06T09:37:15Z-
dc.date.available2010-09-06T09:37:15Z-
dc.date.issued2005en_HK
dc.identifier.citationBiochemistry, 2005, v. 44 n. 32, p. 10784-10795en_HK
dc.identifier.issn0006-2960en_HK
dc.identifier.urihttp://hdl.handle.net/10722/87993-
dc.description.abstractIn 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. © 2005 American Chemical Society.en_HK
dc.languageengen_HK
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_HK
dc.relation.ispartofBiochemistryen_HK
dc.titleFunctional interactions of raf and MEK with Jun-N-terminal kinase (JNK) result in a positive feedback loop on the oncogenic ras signaling pathwayen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-2960&volume=44&issue=32&spage=10784&epage=10795&date=2005&atitle=Functional+interactions+of+Raf+and+MEK+with+Jun-N-Terminal+Kinase+(JNK)+result+in+a+positive+feedback+loop+on+the+oncogenic+Ras+signaling+pathwayen_HK
dc.identifier.emailLin, M:mcllin@hkucc.hku.hken_HK
dc.identifier.authorityLin, M=rp00746en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/bi050619jen_HK
dc.identifier.pmid16086581-
dc.identifier.scopuseid_2-s2.0-23844438832en_HK
dc.identifier.hkuros105172en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-23844438832&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume44en_HK
dc.identifier.issue32en_HK
dc.identifier.spage10784en_HK
dc.identifier.epage10795en_HK
dc.identifier.isiWOS:000231339600005-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridAdler, V=7006627330en_HK
dc.identifier.scopusauthoridQu, Y=7201791381en_HK
dc.identifier.scopusauthoridSmith, SJ=7406648306en_HK
dc.identifier.scopusauthoridIzotova, L=36856382600en_HK
dc.identifier.scopusauthoridPestka, S=7102984042en_HK
dc.identifier.scopusauthoridKung, HF=7402514190en_HK
dc.identifier.scopusauthoridLin, M=7404816359en_HK
dc.identifier.scopusauthoridFriedman, FK=7101617312en_HK
dc.identifier.scopusauthoridChie, L=6602998028en_HK
dc.identifier.scopusauthoridChung, D=7401719222en_HK
dc.identifier.scopusauthoridBoutjdir, M=7003670513en_HK
dc.identifier.scopusauthoridPincus, MR=7101995825en_HK

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