Protein kinase C and beyond

Spitaler, Martin; Cantrell, Doreen A.

doi:10.1038/ni1097

Cited by 276 publications

(232 citation statements)

References 74 publications

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“…Once activated or released from their docking partner PKCs can interact with numerous cellular components. PKCs can interact with the plasma membrane [11], golgi [12], and cytoskeleton [13]. More recently, it has become evident that some PKCs interact with mitochondria [14] and cell nuclei [15].…”

Section: A General Mechanism For Processing and Activation Of Pkcsmentioning

confidence: 99%

Protein kinase C as a stress sensor

Barnett

Madgwick

Takemoto

2007

Cellular Signalling

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While there are many reviews which examine the group of proteins known as protein kinase C (PKC), the focus of this article is to examine the cellular roles of two PKCs that are important for stress responses in neurological tissues (PKCγ and ε) and in cardiac tissues (PKCε). These two kinases, in particular, seem to have overlapping functions and interact with an identical target, connexin 43 (Cx43), a gap junction protein which is central to proper control of signals in both tissues. While PKCγ and PKCε both help protect neural tissue from ischemia, PKCε is the primary PKC isoform responsible for responding to decreased oxygen, or ischemia, in the heart. Both do this through Cx43.It is clear that both PKCγ and PKCε are necessary for protection from ischemia. However, the importance of these kinases has been inferred from preconditioning experiments which demonstrate that brief periods of hypoxia protect neurological and cardiac tissues from future insults, and that this depends on the activation, translocation, or ability for PKCγ and/or PKCε to interact with distinct cellular targets, especially Cx43.This review summarizes the recent findings which define the roles of PKCγ and PKCε in cardiac and neurological functions and their relationships to ischemia/reperfusion injury. In addition, a biochemical comparison of PKC γ and PKC ε and a proposed argument for why both forms are present in neurological tissue while only PKC ε is present in heart, are discussed. Finally, the biochemistry of PKCs and future directions for the field are discussed, in light of this new information.

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Section: A General Mechanism For Processing and Activation Of Pkcsmentioning

confidence: 99%

Protein kinase C as a stress sensor

Barnett

Madgwick

Takemoto

2007

Cellular Signalling

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“…PKC isoforms play pivotal roles in several signal transduction pathways that regulate cellular growth, transformation, differentiation and apoptosis. PKC can be activated by calcium or by various phospholipids, diacylglycerol (DAG), generated by phospholipase C or phospholipase D, and by fatty acids, generated by phospholipase A2, depending on the PKC isoforms [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…However, it is not clear how the isoform-specific subcellular localization and stimulus-induced translocation can be achieved. Probably, PKC binding proteins play important roles in this process and the binding of DAG to C1 domains is also important for the localization of PKC isoforms [2]. Several phorbol esters are analogous to DAG and can bind and activate all PKC isoforms, except the atypical PKC isoforms.…”

Section: Introductionmentioning

confidence: 99%

Isoform-specific translocation of PKC isoforms in NIH3T3 cells by TPA

Kazi

Soh

2007

Biochemical and Biophysical Research Communications

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Protein kinase C (PKC), a multi-gene family of enzymes, plays key roles in the pathways of signal transduction, growth control and tumorigenesis. Variations in the intracellular localization of the individual isoforms are thought to be an important mechanism for the isoform-specific regulation of enzyme activity and substrate specificity. To provide a dynamic method of analyzing the localization of the specific isoforms of PKC in living cells, we generated fluorescent fusion proteins of the various PKC isoforms by using the green fluorescent protein (GFP) as a fluorescent marker at the carboxyl termini of these enzymes. The intracellular localization of the specific PKC isoforms was then examined by fluorescence microscopy after transient transfection of the respective PKC-GFP expression vector into NIH3T3 cells and subsequent TPA stimulation. We found that the specific isoforms of PKC display distinct localization patterns in untreated NIH3T3 cells. For example, PKCα is localized mainly in the cytoplasm while PKCε is localized mainly in the Golgi apparatus. We also observed that PKCα, β1, β2, γ, δ, ε, and η translocate to the plasma membrane within 10 min of the start of TPA treatment, while the cellular localizations of PKCζ and ι were not affected by TPA. Using a protein kinase inhibitor, we also showed that the kinase activity was not important for the translocation of PKC. These results suggest that specific PKC isoforms exert spatially distinct biological effects by virtue of their directed translocation to different intracellular sites.

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“…The constructs used above are schematically depicted in this figure. high levels of PKD1. A further complication is that cells can express multiple DAG-binding proteins including the different DAG kinase isoforms, PKCs, and the Ras guanine nucleotide exchange proteins Ras guanyl nucleotide-releasing proteins (38). DAG availability to PKD1 would inevitably be influenced by the presence of these competing DAG-binding proteins, and DAG might be rate-limiting for PKD1 activation in cells where the ratio of PKD1 to other DAG-binding proteins is low.…”

Section: Figmentioning

confidence: 99%

Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

Wood

Marklund

Cantrell

2005

Journal of Biological Chemistry

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The serine/threonine kinase protein kinase D1 (PKD1) is a protein kinase C (PKC) substrate that mediates antigen receptor signal transduction in lymphocytes. PKC phosphorylates serines 744/748 within the PKD1 catalytic domain, and this is proposed to be necessary and sufficient for enzyme activation. Hence, a PKD1 mutant with alanine substituted at positions 744 and 748 (PKD-S744A/S748A) is catalytically inactive. Conversely, a PKD1 mutant with glutamic residues substituted at positions 744 and 748 as phospho-mimics (PKD-S744E/ S748E) is constitutively active when expressed in Cos7 or HeLa cells. The present study reveals that Ser-744/ Ser-748 phosphorylation is required for PKD1 activation in lymphocytes. However, PKD-S744E/S748E is not constitutively active but, like the wild type enzyme, requires antigen receptor triggering or phorbol ester stimulation. Antigen receptor activation of wild type PKD is dependent on phospholipase C (PLC)/diacylglycerol (DAG) and PKC, whereas PKD-S744E/S748E is only dependent on PLC/DAG but no longer requires PKC. Hence, substitution of serines 744 and 748 with glutamic residues as phospho-mimics bypasses the PKC requirement for PKD1 activation but does not bypass the need for antigen receptors, PLC, or DAG. In lymphocytes, PKD1 is, thus, not regulated by PLC and PKC in a linear pathway; rather, PKD1 activation has more stringent requirements for integration of dual PLC signals, one mediated by PKCs and one that is PKC-independent.

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Protein kinase C and beyond

Cited by 276 publications

References 74 publications

Protein kinase C as a stress sensor

Protein kinase C as a stress sensor

Isoform-specific translocation of PKC isoforms in NIH3T3 cells by TPA

Dual Phospholipase C/Diacylglycerol Requirement for Protein Kinase D1 Activation in Lymphocytes

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