The Sevenfold Way of PKC Regulation

Liu, W.S; Heckman, Carol A.

doi:10.1016/s0898-6568(98)00012-6

Cited by 461 publications

(387 citation statements)

References 163 publications

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“…Consequently chemotaxis, the mechanism by which cells acquire a polarized phenotype in response to a chemoattractant and migrate in a directional manner, has been subject to extensive scrutiny in cancer research. Phorbol esters are able to potently activate protein kinase C (PKC) isoforms by substituting for their natural activator sn-1,2-diacylglycerol (reviewed Liu and Heckman, 1998). In particular, the tumour-promoting phorbol ester phorbol 12-myristate 13-acetate (PMA), has been used in countless studies to determine the cellular actions of PKC.…”

Section: Introductionmentioning

confidence: 99%

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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Cancer progression is associated with enhanced directional cell migration, both of the tumour cells invading into the stroma and stromal cells infiltrating the tumour site. In cell-based assays to study directional cell migration, phorbol esters are frequently used as a chemotactic agent. However, the molecular mechanism by which these activators of protein kinase C (PKC) result in the establishment of a polarized migratory phenotype is not known. Here we show that CD44 expression is essential for chemotaxis towards a phorbol ester gradient. In an investigation of CD44 phosphorylation kinetics in resting and stimulated cells, Ser316 was identified as a novel site of phosphorylation following activation of PKC. PKC does not phosphorylate Ser316 directly, but rather mediates the activation of downstream Ser316 kinase(s). In transfection studies, a phosphorylation-deficient Ser316 mutant was shown to act in a dominant-negative fashion to impair chemotaxis mediated by endogenous CD44 in response to a phorbol ester gradient. Importantly, this mutation had no effect on random cell motility or the ability of cells to migrate directionally towards a cocktail of chemoattractants. These studies demonstrate that CD44 functions to provide directional cues to migrating cells without affecting the motility apparatus.

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Section: Introductionmentioning

confidence: 99%

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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“…[1][2][3] The interaction of PKC isoforms with regulatory proteins determines subcellular localization as well as function. A variety of PKC binding proteins have been identified, including proteins that interact with active PKC, anchoring proteins and substrates.…”

Section: Introductionmentioning

confidence: 99%

“…A variety of PKC binding proteins have been identified, including proteins that interact with active PKC, anchoring proteins and substrates. [2][3][4] In the case of PKCz, binding of Par-4 to the regulatory domain inhibits PKCz activity. 4 Growing evidence indicates that phosphorylation is also a crucial event in regulation of PKC.…”

Section: Introductionmentioning

confidence: 99%

“…PKC phosphorylation is a processing event that regulates maturation of the enzyme, in addition to regulating activation. 2,5 PKCz is phosphorylated at Thr-410 in the activation loop by phosphoinositide-dependent protein kinase-1 (PDK-1), and this phosphorylation is required for activity. PKCz is also phosphorylated at Thr-560, which is an autophosphorylation site.…”

Section: Introductionmentioning

confidence: 99%

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p38 kinase mediates nitric oxide-induced apoptosis of chondrocytes through the inhibition of protein kinase C ζ by blocking autophosphorylation

et al. 2005

Cell Death Differ

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This study investigated the molecular mechanisms underlying inhibition of protein kinase C (PKC) f by p38 kinase during nitric oxide (NO)-induced apoptosis of chondrocytes. Coimmunoprecipitation experiments showed that activation of p38 kinase following addition of an NO donor resulted in a physical association between PKCf and p38 kinase. Direct interaction of p38 kinase with PKCf was confirmed in vitro using p38 kinase and PKCf recombinant proteins. p38 kinase interacts with the regulatory domain of PKCf and its association blocked PKCf autophosphorylation. Micro LC-MS/MS analysis using recombinant proteins indicated that the interaction of p38 kinase with PKCf blocked autophosphorylation of PKCf on Thr-560, which is required for PKCf activation. Collectively, our results demonstrate a novel mechanism of PKCf regulation: following activation by the production of NO, p38 kinase binds directly to the PKCf regulatory domain, preventing PKCf autophosphorylation on Thr-560, thereby inhibiting PKCf activation.

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“…These PKCs are independent of calcium ions, but can be activated by DAGs. Atypical PKCs (aPKCs) include isotypes PKC-z, -l and -t. These PKCs are independent of both calcium ions and DAGs (Liu and Heckman, 1998).…”

Section: Introductionmentioning

confidence: 93%

Activation of protein kinase C suppresses fragmentation of pig oocytes aged in vitro

Petr

Krejčová

Rajmon

et al. 2011

Animal

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When cultured for an extended time, pig oocytes that matured in vitro to the stage of metaphase II undergo the complex process designated as ageing. Under our conditions, some pig oocytes aged 3 days remained at the stage of metaphase II (22%), but others underwent spontaneous parthenogenetic activation (45%), and still others perished through fragmentation (28%) or lysis (5%). Activation of protein kinases C (PKCs) using phorbol-12-myristate-13-acetate (PMA) protects oocytes from fragmentation. None of the oocytes were fragmented after 3 days of aging in 50 nM of PMA. A similar effect (8% of fragmented oocytes) was observed after a 3-day treatment of aging oocytes with 100 mM of 1-stearoyl-2arachidonoyl-sn-glycerol (STEAR). PMA and STEAR activate both calcium-dependent and calcium-independent PKCs. This combined effect on PKCs seems to be essential for the protection of oocytes from fragmentation. Neither the specific activator of calcium-dependent PKCs 1-oleoyl-2-acetyl-sn-glycerol (OLE) nor the specific activator of calcium-independent PKCs dipalmitoyl-L-a-phosphatidylinositol-3,4,5-triphosphate heptaammonium salt (DIPALM) suppressed the fragmentation of aging pig oocytes. Twenty-one percentage of oocytes fragmented when aged for 3 days in 10 mM OLE and 26% of aged oocytes fragmented in 100 nM of DIPALM. However, fragmentation was significantly suppressed to 7% when the oocytes were exposed to the combination of both 10 mM OLE and 100 nM DIPALM. Aging pig oocytes cultured for 1 day with PMA maintained a high capability of being parthenogenetically activated (86% of activated oocytes), using calcium ionophore with 6-dimethylaminopurine. Ageing oocytes treated with PMA also had high capability of cleavage (82%) after their artificial parthenogenetic activation. However, their ability to develop to the stage of blastocyst (12%) was suppressed when compared with oocytes activated immediately after their maturation (29%).

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The Sevenfold Way of PKC Regulation

Cited by 461 publications

References 163 publications

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

p38 kinase mediates nitric oxide-induced apoptosis of chondrocytes through the inhibition of protein kinase C ζ by blocking autophosphorylation

Activation of protein kinase C suppresses fragmentation of pig oocytes aged in vitro

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