Differential Activation of ERK and JNK Mitogen-Activated Protein Kinases by Raf-1 and MEKK

Minden, Audrey; Lin, Anning; McMahon, Martin; Lange, Carol A.; Dérijard, Benoı̂t; Davis, Roger J.; Johnson, Gary L.; Karin, Michael

doi:10.1126/science.7992057

Cited by 1,042 publications

(939 citation statements)

References 36 publications

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“…One possibility is that both the Ras-Raf1-MEK-ERK and Rac-MEKK-SEK-JNK signaling pathways are activated almost simultaneously by bufalin. Signal transduction pathways from Ras to MEK kinase (MEKK) (Minden et al, 1994) and from Ras to Rac (Ridley et al, 1992), albeit indirect pathways, have been reported. In addition, constitutively active MEK1 stimulates JNK in U937 cells (Franklin and Kraft, 1995).…”

Section: Of Results From Three Independent Experimentsmentioning

confidence: 99%

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

et al. 1999

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Bufalin, a component of the Chinese medicine chan'su, induces apoptosis in various lines of human tumor cells, such as leukemia HL60 and U937 cells, by altering the expression of apoptosis-related genes, for example, bcl-2 and c-myc. In this study, we characterized a gene that is involved in bufalin-induced apoptosis by the di erential display (DD) technique. The partial nucleotide sequence of one of the di erentially expressed clones obtained after treatment with bufalin was identical to that of the human gene for Tiam1. When U937 cells were treated with 10 77 M bufalin, expression of both Tiam1 mRNA and the protein was induced 1 h after the start of the treatment. The increase of Tiam1 mRNA was transient but the level of Tiam1 protein continued to increase at least for 6 h. In addition, the activities of Rac1 and p21-activated kinase (PAK) were also stimulated by bufalin treatment. To evaluate the role of Tiam1 in the apoptotic process, we examined the e ects of the expression of sense and antisense RNA for Tiam1 in U937 cells. Apoptosis was strongly induced by bufalin in cells that expressed sense RNA for Tiam1 as compared to apoptosis in control cells treated with bufalin only. Cells expressing antisense RNA for Tiam1 were signi®cantly more resistant than the control bufalin-treated cells to induction of DNA fragmentation in response to bufalin. Moreover, sense transformants had elevated activities of PAK and c-Jun NH 2 -terminal kinase (JNK). These results suggest that Tiam1 might play a critical role in bufalin-induced apoptosis through the activation of Rac1, PAK, and JNK pathway.

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Section: Of Results From Three Independent Experimentsmentioning

confidence: 99%

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

et al. 1999

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“…Another possibility is that activation of other kinases, like the Jun kinases, in the 250phe mutant may be responsible for AP-1 activation in this cell line. Di erential mechanisms for ERK and JNK activation (Minden et al, 1994) as well as activation of JNK by oncogenes such as Ras and Src have already been described (Hibi et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Mapping of polyomavirus middle T domain that is responsible for AP-1 activation

et al. 1998

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Cell transformation by Polyomavirus middle T (MT) oncoprotein involves binding and activation of several cytoplasmic proteins that participate in growth factorsinduced mitogenic signal transduction to the nucleus. We have previously reported that the AP-1 transcriptional complex is a target for MT during cell transformation. To analyse the interactions between MT and cellular proteins that are required for constitutive AP-1 activation, we compared wild type and transformation-defective MT mutant cell lines. High AP-1 activity, assessed by gel mobility shift assays, displayed by MT-overexpressing cells, is dependent on MT binding to phosphatidylinositol-3 kinase (P13K). Treatment with wortmannin (a speci®c P13K inhibitor) leads to decreased AP-1 activity. Supershift and Western blot analysis with speci®c antisera, indicate that JunB and cJun, but not cFos or FosB are present in the AP-1 complex. The results con®rm the AP-1 complex as a downstream MT target and indicate that AP-1 activation may not be su cient for cell transformation, since two transformation-defective MT mutants (250phe and MT322) display high AP-1 activity.

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“…MEK1 and MEK2 are responsible for the activation of the ERKs, MKK3 and MKK6 for p38, and MKK4 (also referred to as SEK or JNKK1) for JNKs (Minden et al, 1994;Sanchez et al, 1994; reviewed by Karin, 1995). ERKs, in turn, are able to regulate the activity of enzymes and of nuclear proteins such as the ternary complex factor Elk-1, involved in cell proliferation control (reviewed by .…”

Section: Introductionmentioning

confidence: 99%

“…ERKs, in turn, are able to regulate the activity of enzymes and of nuclear proteins such as the ternary complex factor Elk-1, involved in cell proliferation control (reviewed by . On the other side, the two principal isoforms of JNKs, JNK1 and JNK2, were identi®ed by their ability to bind and phosphorylate the amino-terminal (serines 63 and 73) domain of c-Jun (Hibi et al, 1993;Minden et al, 1994;Kyriakis et al, 1994;Derijard et al, 1994). Moreover, activated JNKs are able to phosphorylate at least two other transcription factors, such as ATF-2 (Gupta et al, 1995) and Elk-1 (Whitmarsh et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…TPA (12-O-tetradecanoyl phorbol-13-acetate), which is a potent ERK activator, has little e ect on JNK activity . Ras, which is a potent ERK activator, raises JNK activity only to a limited extent, and, on the other side, Rac1 and Cdc42 small GTPases e ciently stimulate the JNK pathway without a ecting ERK activity (Coso et al, 1995a;Minden et al, 1994Minden et al, , 1995. Accordingly, exchange factors (GEF) for Rac1 and Cdc42 potently induce JNK activity and negative modulators (RhoGAPp190 and RhoGDI) or dominant negative mutants for Rac1 and Cdc42 (N17Rac1 and N17Cdc42) e ectively reduce JNK stimulation by EGF (Coso et al, 1995a;Minden et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

et al. 1998

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The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH 2 -terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 ®broblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-de®cient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.

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Differential Activation of ERK and JNK Mitogen-Activated Protein Kinases by Raf-1 and MEKK

Cited by 1,042 publications

References 36 publications

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

Tiam1 is involved in the regulation of bufalin-induced apoptosis in human leukemia cells

Mapping of polyomavirus middle T domain that is responsible for AP-1 activation

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

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