A novel 50 kDa protein forms complexes with protein phosphatase 4 and is located at centrosomal microtubule organizing centres

Hastie, Claire; Carnegie, Graeme K.; Morrice, Nick; Cohen, Philip

doi:10.1042/bj3470845

Cited by 49 publications

(46 citation statements)

References 44 publications

(21 reference statements)

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“…Unlike PP2A, PP4/PPX is expressed at very low levels in skeletal muscle (35,36), whereas PP7 appears to be limited to retinal cells and is dependent on magnesium (37). Although PP5 is ubiquitous and stimulated by polyunsaturated fatty acids, neither saturated fatty acids, including palmitate, nor ceramide are able to activate this enzyme (38,39).…”

Section: Discussionmentioning

confidence: 99%

A Role for Protein Phosphatase 2A–Like Activity, but Not Atypical Protein Kinase Cζ, in the Inhibition of Protein Kinase B/Akt and Glycogen Synthesis by Palmitate

et al. 2001

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We have shown previously that palmitate treatment of C2C12 skeletal muscle myotubes causes inhibition of the protein kinase B (PKB) pathway and hence reduces insulin-stimulated glycogen synthesis through the elevation of intracellular ceramide levels. Ceramide is known to activate both atypical protein kinase C (aPKC) and protein phosphatase (PP) 2A, and each of these effectors has been reported to inhibit PKB. In the present study, palmitate pretreatment was found to elevate PP2A-like activity in myotubes and to prevent its inhibition by insulin. Incubation with the phosphatase inhibitor okadaic acid before insulin stimulation protected against the effect of the fatty acid on PKB phosphorylation. Palmitate was unable to inhibit PKB activity and glycogen synthesis in cells overexpressing the activated PKB mutant (T308D,S473D)-PKB␣, which is unaffected by phosphatase. In contrast, PKB activity and glycogen synthesis were still inhibited by palmitate in cells overexpressing a membrane-targeted and, hence, activated PKB mutant that retains sensitivity to phosphatase. Although aPKC activity was also increased in palmitate-treated cells, overexpression of wild-type or kinase-dead aPKC did not alter the inhibitory effects of the lipid on either stimulation of PKB or glycogen synthesis by insulin. We conclude that palmitate disrupts insulin signaling in C2C12 myotubes by promoting PP2A-like activity and, therefore, the dephosphorylation of PKB, which in turn reduces the stimulation of glycogen synthesis.

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Section: Discussionmentioning

confidence: 99%

A Role for Protein Phosphatase 2A–Like Activity, but Not Atypical Protein Kinase Cζ, in the Inhibition of Protein Kinase B/Akt and Glycogen Synthesis by Palmitate

et al. 2001

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“…Although in the past, it is the kinases that have been most intensively studied, considerable attention has PP4 (previously known as protein phosphatase X (PPX)), a member of the PP2A family of serine/threonine protein phosphatases, 14,15 has already been implicated in cell regulation, particularly in the centrosome. [25][26][27] Here, we have presented a series of observations that strongly implicate PP4 in the regulation of apoptosis induced either by irradiation or by dexamethasone. Although the effect of PP4 on apoptosis could be mediated through a number of novel or suggested targets, [7][8][9][10][11][12]18 the reported interaction with c-Rel and other NF-kB proteins is of particular interest.…”

Section: Discussionmentioning

confidence: 99%

Functional expression cloning reveals proapoptotic role for protein phosphatase 4

et al. 2003

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Functional expression cloning strategies are highly suitable for the analysis of the molecular control of apoptosis. This approach has two critical advantages. Firstly, it eliminates prior assumptions about the properties of the proteins involved, and, secondly, it selectively targets proteins that are causally involved in apoptosis control and which affect the crucial cellular decision between survival and death. The application of this strategy to the isolation of cDNAs conferring resistance to dexamethasone and c-irradiation resulted in the isolation of a partial cDNA for the catalytic subunit of protein phosphatase 4 (PP4). Cells transfected with this partial cDNA in an expression vector downregulated PP4 and were resistant to both dexamethasone and UV radiation, as demonstrated by both membrane integrity and colonyforming assays. These observations suggest that PP4 plays an important proapoptotic role in T lymphocytes.

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“…The core dimer binds additional regulatory subunits that target PP2A to specific substrates [25,26]. The mammalian PP4 catalytic subunit also interacts with scaffold and regulatory subunits [27,28], while PP6 regulatory proteins have been identified in yeast [29]. Due to decreased complexity relative to mammalian cells, Drosophila has been a valuable system to study functions of individual catalytic and regulatory subunits within the PP2A subfamily [30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of the PP2A subfamily of protein phosphatases in regulating Drosophila S6 kinase

Bielinski¹,

Mumby²

2007

Experimental Cell Research

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Phosphorylation and activation of ribosomal S6 protein kinase is an important link in the regulation of cell size by the target of rapamycin (TOR) protein kinase. A combination of selective inhibition and RNA interference were used to test the roles of members of the PP2A subfamily of protein phosphatases in dephosphorylation of Drosophila S6 kinase (dS6K). Treatment of Drosophila Schneider 2 cells with calyculin A, a selective inhibitor of PP2A-like phosphatases, resulted in a 7-fold increase in the basal level of dS6K phosphorylation at the TOR phosphorylation site (Thr398) and blocked dephosphorylation following inactivation of TOR by amino acid starvation or rapamycin treatment. Knockdown of the PP2A catalytic subunit increased basal dS6K phosphorylation and inhibited dephosphorylation induced by amino acid withdrawal. In contrast, depletion of the catalytic subunits of the other two members of the subfamily did not enhance dS6K phosphorylation. Knockdown of PP4 caused a 20% decrease in dS6K phosphorylation and knockdown of PP6 had no effect. Knockdown of the Drosophila B56-2 subunit resulted in enhanced dephosphorylation of dS6K following removal of amino acids. In contrast, knockdown of the homologs of the other PP2A regulatory subunits had no effects. Knockdown of the Drosophila homolog of the PP2A/PP4/PP6 interaction protein α4/Tap42 did not affect S6K phosphorylation, but did induce apoptosis. These results indicate that PP2A, but not other members of this subfamily, is likely to be a major S6K phosphatase in intact cells and is consistent with an important role for this phosphatase in the TOR pathway.

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A novel 50 kDa protein forms complexes with protein phosphatase 4 and is located at centrosomal microtubule organizing centres

Cited by 49 publications

References 44 publications

A Role for Protein Phosphatase 2A–Like Activity, but Not Atypical Protein Kinase Cζ, in the Inhibition of Protein Kinase B/Akt and Glycogen Synthesis by Palmitate

A Role for Protein Phosphatase 2A–Like Activity, but Not Atypical Protein Kinase Cζ, in the Inhibition of Protein Kinase B/Akt and Glycogen Synthesis by Palmitate

Functional expression cloning reveals proapoptotic role for protein phosphatase 4

Functional analysis of the PP2A subfamily of protein phosphatases in regulating Drosophila S6 kinase

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