Protein Kinase C δ Activates the MEK-ERK Pathway in a Manner Independent of Ras and Dependent on Raf

Ueda, Yoshihiko; Hirai, Syu-ichi; Osada, Shin‐Ichi; Suzuki, Atsushi; Mizuno, Keiko; Ohno, Shigeo

doi:10.1074/jbc.271.38.23512

Cited by 527 publications

(400 citation statements)

References 61 publications

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“…PKCa isozyme was shown to activate Raf-1 by direct phosphorylation (Kolch et al, 1993). Ueda et al (1996) showed that PKCd is a possible activator of the MAP kinase pathway in COS cells in a Ras-independent manner, by using a constitutively active mutant of PKCd. In a recent report, PKCe was implicated in signaling of cell proliferation by activating Raf-1 in NIH3T3 cells (Cai et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells

1999

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Section: Discussionmentioning

confidence: 99%

VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells

1999

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“…Cells expressing the kinase-dead PKC ␣ were generated as described previously (7). The kinase-dead PKC ␣ clone was generated by a mutation to the ATP-binding site as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

Activation of Protein Kinase C Triggers Its Ubiquitination and Degradation

Liu

Hornia

et al. 1998

Molecular and Cellular Biology

307

256

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Treatment of cells with tumor-promoting phorbol esters results in the activation but then depletion of phorbol ester-responsive protein kinase C (PKC) isoforms. The ubiquitin-proteasome pathway has been implicated in regulating the levels of many cellular proteins, including those involved in cell cycle control. We report here that in 3Y1 rat fibroblasts, proteasome inhibitors prevent the depletion of PKC isoforms ␣, ␦, and in response to the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Proteasome inhibitors also blocked the tumor-promoting effects of TPA on 3Y1 cells overexpressing c-Src, which results from the depletion of PKC ␦. Consistent with the involvement of the ubiquitin-proteasome pathway in the degradation of PKC isoforms, ubiquitinated PKC ␣, ␦, and were detected within 30 min of TPA treatment. Diacylglycerol, the physiological activator of PKC, also stimulated ubiquitination and degradation of PKC, suggesting that ubiquitination is a physiological response to PKC activation. Compounds that inhibit activation of PKC prevented both TPA-and diacylglycerol-induced PKC depletion and ubiquitination. Moreover, a kinase-dead ATP-binding mutant of PKC ␣ could not be depleted by TPA treatment. These data are consistent with a suicide model whereby activation of PKC triggers its own degradation via the ubiquitin-proteasome pathway.Tumor promotion by phorbol esters involves the selective amplification of cells previously mutated in an appropriate growth-stimulatory gene (3,17). Phorbol esters exert their effects on the protein kinase C (PKC) family of genes, which consists of genes that encode at least nine distinct isoforms that are responsive to tumor-promoting phorbol esters (9). Phorbol esters first activate phorbol ester-responsive PKC isoforms, but upon prolonged treatment, these isoforms are proteolytically degraded (16). Using a cell culture model system in which cells overexpressing c-Src were transformed by phorbol ester treatment, we recently demonstrated that the tumor-promoting effect of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) on these cells was due to the depletion of PKC ␦ (7). These data suggested that PKC ␦ may function as a tumor suppressor. Consistent with this hypothesis, PKC ␦ was inactivated by tyrosine phosphorylation in cells transformed by v-Src (19) and v-Ras (2). Thus, regulation of PKC ␦ at the level of activity and expression may be a very important cell growth control mechanism.PKC ␣ has been reported to become ubiquitinated in response to bryostatin 1, an activator of PKC that prevents tumor promotion in mouse skin by TPA (6). The ubiquitin-proteasome pathway is a nonlysosomal degradation system that controls the timed destruction of cell cycle-regulatory proteins, including the tumor suppressor p53; the cyclin-dependent kinase inhibitor p27; the cyclins; the oncogene products c-Myc, c-Jun, and c-Fos; and the transcription factors NF-B and E2F (reviewed in reference 13). This pathway involves the covalent tagging of proteins with u...

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“…The PKC pathway is another mechanism by which ERK and p38 are activated (Ueda et al, 1996;Schonwasser et al, 1998). To determine whether such a mechanism could account for the activation of ERK by 4HPR, we used the pan-selective PKC inhibitor GF109203X.…”

Section: Implication Of Pkc In Activation Of Erk and P38 By 4hprmentioning

confidence: 99%

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

et al. 2006

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Protein Kinase C δ Activates the MEK-ERK Pathway in a Manner Independent of Ras and Dependent on Raf

Cited by 527 publications

References 61 publications

VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells

VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells

Activation of Protein Kinase C Triggers Its Ubiquitination and Degradation

N-(4-Hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells

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