PKC-interacting proteins: from function to pharmacology. Trends Pharmacol Sci

Department of Pharmacology, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 11/2004; 25(10):528-35. DOI: 10.1016/
Source: PubMed


Protein kinase C (PKC) is a ubiquitously expressed family of kinases that have key roles in regulating multiple cellular activities. The activity of this family is controlled tightly by several molecular mechanisms, including interaction with binding-partner proteins. These PKC-interacting proteins (C-KIPs) confer specificity for individual PKC isoforms by regulating the activity and cellular localization of PKC isoforms and, subsequently, the ability of these isoforms to specifically regulate cellular functional events. Although many C-KIPs have been identified by genome and proteome-mining approaches, it is important to address the specificity and function of the interactions in greater detail because they might form novel drug targets. In this article, we review recent work on C-KIPs and the implications for pharmacological and therapeutic development.

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    • "Besides the differences in their activation , PKC isoforms differ in their structure, tissue distribution and subcellular localization [8] [9]. The latter is influenced by the activation status and by the interaction with molecules [10] such as RACKs/RICKs (receptors for activated/inactive kinase) [11] [12], PICK1 (protein interacting with C-kinase-1) [13] [14] and STICKs (substrates interacting with C kinase) [15]. Activated PKCs interact with signaling pathways that regulate cell survival and differentiation such as MEK–ERK, Raf1 and c-Jun [16] as well as STAT1, STAT3 and NF-κB [17] [18] [19] [20] [21] [22]. "
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    ABSTRACT: PKC activation by combining TPA with sodium butyrate (T/B) represents the most effective and widely used strategy to induce the Epstein-Barr virus (EBV) lytic cycle. The results obtained in this study show that novel PKCθ is involved in such process and that it acts through the activation of p38 MAPK and autophagy induction. Autophagy, a mechanism of cellular defense in stressful conditions, is manipulated by EBV to enhance viral replication. Besides promoting the EBV lytic cycle, the activation of p38 and autophagy resulted in a pro-survival effect, as indicated by p38 or ATG5 knocking down experiments. However, this pro-survival role was counteracted by a pro-death activity of PKCθ, due to the dephosphorylation of AKT. In conclusion, this study reports, for the first time, that T/B activates a PKCθ-p38 MAPK axis in EBV infected B cells, that promotes the viral lytic cycle and cell survival and dephosphorylates AKT, balancing cell life and cell death. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 03/2015; 1853(7). DOI:10.1016/j.bbamcr.2015.03.011 · 4.66 Impact Factor
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    • "Another intriguing possibility is that EtOH may target PKC isozyme-specific interacting proteins present in the membrane fraction. Indeed, a number of PKC isozymespecific interacting proteins have been identified, which might regulate PKC activity (Poole et al, 2004). In this regard, EtOH has been shown to promote the uncoupling of the scaffolding protein, RACK1, from PKCb 2 (Ron et al, 2000). "
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    ABSTRACT: Ethanol consumption potentiates dopaminergic signaling that is partially mediated by the D(1) dopamine receptor; however, the mechanism(s) underlying ethanol-dependent modulation of D(1) signaling is unclear. We now show that ethanol treatment of D(1) receptor-expressing cells decreases D(1) receptor phosphorylation and concurrently potentiates dopamine-stimulated cAMP accumulation. Protein kinase C (PKC) inhibitors mimic the effects of ethanol on D(1) receptor phosphorylation and dopamine-stimulated cAMP levels in a manner that is non-additive with ethanol treatment. Ethanol was also found to modulate specific PKC activities as demonstrated using in vitro kinase assays where ethanol treatment attenuated the activities of lipid-stimulated PKCgamma and PKCdelta in membrane fractions, but did not affect the activities of PKCalpha, PKCbeta(1), or PKCvarepsilon. Importantly, ethanol treatment potentiated D(1) receptor-mediated DARPP-32 phosphorylation in rat striatal slices, supporting the notion that ethanol enhances D(1) receptor signaling in vivo. These findings suggest that ethanol inhibits the activities of specific PKC isozymes, resulting in decreased D(1) receptor phosphorylation and enhanced dopaminergic signaling.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2008; 33(12):2900-11. DOI:10.1038/npp.2008.16 · 7.05 Impact Factor
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    • "o trigger novel PKCs , their C2 domain contains other targeting sequences involved in activation or subcellular translocation ( Table 1 ) ( Giorgione et al . 2006 ; Zhu et al . 2006 ) . While tyrosine phosphorylation is an important driving factor in PKCd ( Steinberg 2004 ) , RACK binding contributes to uncover the kinase domain PKCe ( Fig . 2 ) ( Poole et al . 2004 ; Schechtman et al . 2004 ; Brandman et al . 2007 ) . This RACK has been identified as b¢ - coatomer protein , a coatomer protein I complex protein associated to Golgi"
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    ABSTRACT: Despite the apparent homology in the protein kinase C (PKC) family, it has become clear that slight structural differences are sufficient to have unique signalling properties for each individual isoform. For PKCepsilon in depth investigation of these aspects revealed unique actions in the CNS and lead to development of specific modulators with clinical perspective. In this review, we describe to which extent PKCepsilon is distinct from other isoforms on the level of tissue expression and protein structure. As this kinase is highly expressed in the brain, we outline three main aspects of PKCepsilon signalling in the CNS. First, its ability to alter the permeability of N-type Ca2+ channels in dorsal root ganglia has been shown to enhance nociception. Secondly, PKCepsilon increases anxiety by diminishing GABA(A)R-induced inhibitory post-synaptic currents in the prefrontal cortex. Another important aspect of the latter inhibition is the reduced sensitivity of GABA(A) receptors to ethanol, a mechanism potentially contributing to abuse. A third signalling cascade improves cognitive functions by facilitating cholinergic signalling in the hippocampus. Collectively, these findings point to a physical and behavioural sensitising role for this kinase.
    Journal of Neurochemistry 02/2008; 104(1):1-13. DOI:10.1111/j.1471-4159.2007.04986.x · 4.28 Impact Factor
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