Phosphorylation of Protein Kinase Cδ on Distinct Tyrosine Residues Regulates Specific Cellular Functions

Kronfeld, Ilana; Kazimirsky, Gila; Lorenzo, Patricia S.; Garfield, Susan H.; Blumberg, Peter M.; Brodie, Chaya

doi:10.1074/jbc.m005991200

Cited by 110 publications

(125 citation statements)

References 43 publications

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“…To detect tyrosine-phosphorylated PKC␦, total cell lysates were immunoprecipitated with anti-phosphotyrosine antibody followed by immunoblotting with anti-PKC␦ antibody. Consistent with previous reports (24,25), PDGF induced tyrosine phosphorylation of PKC␦ with biphasic kinetics (5 min, 4.2-fold; 18 h, 2.1-fold induction) similar to that seen for PKC␦ activity (Fig. 7A).…”

Section: Overexpression Of Pkc␦ Reversed the Inhibitory Effects Of Ppsupporting

confidence: 80%

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Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Wakino¹,

Kintscher²,

Liu³

et al. 2001

Journal of Biological Chemistry

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The cyclin-dependent kinase inhibitor p21Cip1 is upregulated in response to mitogenic stimulation in various cells. PPAR␥ ligands troglitazone (TRO, 10 M) and rosiglitazone (RSG, 10 M) attenuated the induction of p21Cip1 protein by platelet-derived growth factor (PDGF) and insulin without affecting cognate mRNA levels in rat aortic smooth muscle cells (RASMC). The protein kinase C␦ (PKC␦) inhibitor rottlerin also blocked the induction of p21Cip1 protein, whereas the conventional PKC isotype inhibitor Gö 6976 had no effect. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that TRO, RSG, and rottlerin shortened the half-life of p21 Cip1 expression in PDGFtreated RASMC. PPAR␥ ligands enhanced proteintyrosine-phosphatase activity in RASMC, which may be the mechanism for decreased PKC␦ tyrosine phosphorylation and activity. PPAR␥ ligands regulate p21Cip1 at a post-translational level by blocking PKC␦ signaling and accelerating p21Cip1 turnover.Vascular smooth muscle cells (VSMC) 1 in the normal vessel wall proliferate at a very low frequency. Injury to the endothelium results in the release of mitogens that stimulate quiescent, G 0 /G 1 -arrested VSMC to reenter the cell cycle, replicate DNA, and divide. VSMC hyperplasia is a key event in the formation of restenotic and atherosclerotic lesions in the vasculature (1, 2). Cyclin-dependent kinases (CDKs) are serinethreonine protein kinases that regulate cell cycle progression after forming complexes with and being activated by cyclins (3). Mitogenic activation of cyclin D⅐CDK4, cyclin D⅐CDK6, and cyclin E⅐CDK2 during the G 1 phase results in phosphorylation of retinoblastoma gene (Rb) proteins. In its hyperphosphorylated state, Rb functions as a gatekeeper for the G 1 3 S transition by binding and sequestering E2F, a transcription factor that induces the expression of a battery of genes that encode the enzymatic machinery for S phase DNA synthesis. Cyclindependent kinase inhibitors (CDKIs) can negatively regulate the mitogen-induced cascade of G 1 events by inhibiting CDK activity and preventing Rb phosphorylation (3, 4).Consistent with the view that CDKIs are major negative regulators of the cell cycle, overexpression of Cip/Kip family members (p21 Cip1 , p27 Kip1 ) blocks the G 1 exit in VSMC and other cell types (5, 6). Data emerging from recent studies, however, suggest that CDKIs p21Cip1 and p27 Kip1 can also function as positive regulators during the G 1 phase as assembly factors to promote formation of cyclin⅐CDK holoenzyme complexes (3, 7). Such a role for CDKIs may explicate apparent paradoxical observations that p21Cip1 is frequently up-regulated after mitogenic stimulation of quiescent cells (8,9). In rat VSMC cell lines, prevention of mitogen-induced p21 Cip1 expression by antisense oligodeoxynucleotides attenuated both DNA synthesis and cell proliferation (10). We recently reported that ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR␥) inhibited Rb phosphorylation and G 1 3 S transition in ra...

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Section: Overexpression Of Pkc␦ Reversed the Inhibitory Effects Of Ppsupporting

confidence: 80%

“…6C). (22)(23)(24)(25). In some systems, tyrosine phosphorylation of PKC␦ induces serine/threonine kinase activity of PKC␦.…”

Section: Overexpression Of Pkc␦ Reversed the Inhibitory Effects Of Ppmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Wakino¹,

Kintscher²,

Liu³

et al. 2001

Journal of Biological Chemistry

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“…When overexpressed, it can slow the growth of fibroblasts (Mischak et al, 1993), and inhibit morphological transformation in a variety of systems (Li et al, 1996;Perletti et al, 1999). PKCd is phosphorylated on tyrosine residues in response to several different stimuli, usually as a result of SFK activity (Li et al, 1994;Denning et al, 1996;Blake et al, 1999;Kronfeld et al, 2000;Joseloff et al, 2002). SFKs processively phosphorylate several tyrosines on PKCd (with Tyr 311 being the first residue phosphorylated), and this causes the subsequent degradation of the protein.…”

Section: Other Sfk Mitogenic Targetsmentioning

confidence: 99%

The interplay between Src family kinases and receptor tyrosine kinases

2004

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Src family tyrosine kinases (SFKs) are involved in a diverse array of physiological processes, as highlighted in this review. An overview of how SFKs interact with, and participate in signaling from, receptor tyrosine kinases (RTKs) is discussed. And also, how SFKs are activated by RTKs, and how SFKs, in turn, can activate RTKs, as well as how SFKs can promote signaling from growth factor receptors in a number of ways including participation in signaling pathways required for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangements and motility, and survival are discussed.

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“…In contrast, overexpression of PKC␦ inhibited the proliferation of fibroblasts (31), induced monocytic differentiation of the myeloid progenitor cell line (17), and enhanced enterocyte-like differentiation of colon cancer cell line Caco-2 (28). PKC␦ has been reported to undergo tyrosine phosphorylation in response to various stimuli such as PMA, epidermal growth factor, and PDGF (17,32,33). TNF␣ has been shown to induce NF-B activation through PKC␦ in human neutrophils (34).…”

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confidence: 99%

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Wang

Evers

2003

Journal of Biological Chemistry

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Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca 2؉ -independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC␦-selective inhibitor rottlerin or transfection with an antisense PKC␦ oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC␦ plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC␦ in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMAinduced NF-B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC␦-induced cIAP-2 promoter activity and increased NF-B transactivation, suggesting regulation of cIAP-2 expression by a PKC␦/NF-B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC␦/NF-B/cIAP-2 pathway in certain cancers.

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Phosphorylation of Protein Kinase Cδ on Distinct Tyrosine Residues Regulates Specific Cellular Functions

Cited by 110 publications

References 43 publications

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

The interplay between Src family kinases and receptor tyrosine kinases

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

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