Limits...
Cell signaling through protein kinase C oxidation and activation.

Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR - Int J Mol Sci (2012)

Bottom Line: In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events.The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox-sensitive cysteine residues.These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Biochemistry, Federal University of Rio de Janeiro (UFRJ), CCS, Bloco H, Cidade Universitária, Ilha do Fundão, 21941-590, Rio de Janeiro, RJ, Brazil; E-Mails: rocco@bioqmed.ufrj.br (N.R.-M.); meyer@bioqmed.ufrj.br (J.R.M.-F.) ; Institute of National Science and Technology of Structural Biology and Bioimage (INCTBEB), CCS, Bloco H, Cidade Universitária, Ilha do Fundão, 21941-590, Rio de Janeiro, RJ, Brazil.

ABSTRACT
Due to the growing importance of cellular signaling mediated by reactive oxygen species (ROS), proteins that are reversibly modulated by these reactant molecules are of high interest. In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox-sensitive cysteine residues. Protein kinase C (PKC) is involved in a variety of cellular signaling pathways. These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification. A large number of scientific studies have highlighted the importance of ROS as a second messenger in numerous cellular processes, including cell proliferation, gene expression, adhesion, differentiation, senescence, and apoptosis. In this context, the goal of this review is to discuss the mechanisms by which PKCs are modulated by ROS and how these processes are involved in the cellular response.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of susceptible sites to oxidation of PKCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3472709&req=5

f2-ijms-13-10697: Schematic representation of susceptible sites to oxidation of PKCs.

Mentions: In the PKC structure, two pairs of zinc fingers are found within the regulatory domain. They are sites of DAG and phorbol ester binding. Each zinc finger is formed by a structure that is composed of six cysteine residues and two zinc atoms, as presented in Figure 2. The high levels of cysteine residues render the regulatory domain susceptible to redox regulation [11,23]. The oxidants destroy the zinc finger conformation [38], and the autoinhibition is relieved, resulting in a PKC form that is catalytically active in the absence of Ca2+ or phospholipids. Cysteine residues are also found in the C-terminal catalytic domain, but they are uncoordinated in a different manner to those in the regulatory domain. Redox modifications at the C-terminal catalytic domain lead to the inactivation of the kinase due to the loss of the free sulfhydryls required for its catalytic activity. Furthermore, the intracellular redox state has been shown to affect the distribution of the PKC isoforms [11,23]. Because all PKC isoforms possess zinc fingers and high concentration of cysteine residues located in the regulatory domain, as well as free sulfhydryls in the catalytic site, it seems that the regulation by oxidation is a common feature for this family. However, this signaling mechanism may vary according to the distinct isoform and different cell [11]. The aPKCs, for example, lack one of the two cysteine-rich zinc-finger regions in the regulatory domain [39]. This characteristic can render aPKCs to a distinct susceptibility of oxidative stress. In mouse embryonic fibroblasts, oxidative stress triggers translocation of PKCα, β, δ, and ɛ isoforms from the cytosol to the plasma membrane. Nevertheless, under the same conditions, PKCζ translocates to the nucleus [11]. PKCδ selectively regulates the activation of the inducible nuclear factor κB (NF-κB) in response to oxidative stress. The activation of the transcription factor NF-κB is often observed in cells exposed to oxidative stress [40]. In HeLa cells treated with exogenous H2O2 this signaling pathway was shown to be dependent of the activation of PKD by two coordinated signaling events: the phosphorylation of Tyr463 mediated by the Src-Abl signaling pathway, which then facilitates the second step, the phosphorylation of the PKD activation loop of Ser738/Ser742 by the Src-PKCδ pathway, leading to an increase in cell survival exposed to oxidative stress [41,42]. This coordinated mechanism seems to be specifically in response to oxidative stress, and relies on the activation of PKCδ and not of other PKC isoforms [41]. Later the same group showed that the resveratrol-dependent inhibition of PKD Ser738/Ser742 phosphorylation by PKCδ was able to block the activation of NF-κB in response to oxidative stress. Resveratrol inhibited NFκB activation by avoiding PKD association with IKK complex [40]. The specificity by which ROS may activate different PKC isoforms is not well established, but the localization and the intensity of ROS generation could contribute to the explanation of such different responses.


Cell signaling through protein kinase C oxidation and activation.

Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR - Int J Mol Sci (2012)

Schematic representation of susceptible sites to oxidation of PKCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472709&req=5

f2-ijms-13-10697: Schematic representation of susceptible sites to oxidation of PKCs.
Mentions: In the PKC structure, two pairs of zinc fingers are found within the regulatory domain. They are sites of DAG and phorbol ester binding. Each zinc finger is formed by a structure that is composed of six cysteine residues and two zinc atoms, as presented in Figure 2. The high levels of cysteine residues render the regulatory domain susceptible to redox regulation [11,23]. The oxidants destroy the zinc finger conformation [38], and the autoinhibition is relieved, resulting in a PKC form that is catalytically active in the absence of Ca2+ or phospholipids. Cysteine residues are also found in the C-terminal catalytic domain, but they are uncoordinated in a different manner to those in the regulatory domain. Redox modifications at the C-terminal catalytic domain lead to the inactivation of the kinase due to the loss of the free sulfhydryls required for its catalytic activity. Furthermore, the intracellular redox state has been shown to affect the distribution of the PKC isoforms [11,23]. Because all PKC isoforms possess zinc fingers and high concentration of cysteine residues located in the regulatory domain, as well as free sulfhydryls in the catalytic site, it seems that the regulation by oxidation is a common feature for this family. However, this signaling mechanism may vary according to the distinct isoform and different cell [11]. The aPKCs, for example, lack one of the two cysteine-rich zinc-finger regions in the regulatory domain [39]. This characteristic can render aPKCs to a distinct susceptibility of oxidative stress. In mouse embryonic fibroblasts, oxidative stress triggers translocation of PKCα, β, δ, and ɛ isoforms from the cytosol to the plasma membrane. Nevertheless, under the same conditions, PKCζ translocates to the nucleus [11]. PKCδ selectively regulates the activation of the inducible nuclear factor κB (NF-κB) in response to oxidative stress. The activation of the transcription factor NF-κB is often observed in cells exposed to oxidative stress [40]. In HeLa cells treated with exogenous H2O2 this signaling pathway was shown to be dependent of the activation of PKD by two coordinated signaling events: the phosphorylation of Tyr463 mediated by the Src-Abl signaling pathway, which then facilitates the second step, the phosphorylation of the PKD activation loop of Ser738/Ser742 by the Src-PKCδ pathway, leading to an increase in cell survival exposed to oxidative stress [41,42]. This coordinated mechanism seems to be specifically in response to oxidative stress, and relies on the activation of PKCδ and not of other PKC isoforms [41]. Later the same group showed that the resveratrol-dependent inhibition of PKD Ser738/Ser742 phosphorylation by PKCδ was able to block the activation of NF-κB in response to oxidative stress. Resveratrol inhibited NFκB activation by avoiding PKD association with IKK complex [40]. The specificity by which ROS may activate different PKC isoforms is not well established, but the localization and the intensity of ROS generation could contribute to the explanation of such different responses.

Bottom Line: In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events.The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox-sensitive cysteine residues.These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Biochemistry, Federal University of Rio de Janeiro (UFRJ), CCS, Bloco H, Cidade Universitária, Ilha do Fundão, 21941-590, Rio de Janeiro, RJ, Brazil; E-Mails: rocco@bioqmed.ufrj.br (N.R.-M.); meyer@bioqmed.ufrj.br (J.R.M.-F.) ; Institute of National Science and Technology of Structural Biology and Bioimage (INCTBEB), CCS, Bloco H, Cidade Universitária, Ilha do Fundão, 21941-590, Rio de Janeiro, RJ, Brazil.

ABSTRACT
Due to the growing importance of cellular signaling mediated by reactive oxygen species (ROS), proteins that are reversibly modulated by these reactant molecules are of high interest. In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox-sensitive cysteine residues. Protein kinase C (PKC) is involved in a variety of cellular signaling pathways. These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification. A large number of scientific studies have highlighted the importance of ROS as a second messenger in numerous cellular processes, including cell proliferation, gene expression, adhesion, differentiation, senescence, and apoptosis. In this context, the goal of this review is to discuss the mechanisms by which PKCs are modulated by ROS and how these processes are involved in the cellular response.

No MeSH data available.


Related in: MedlinePlus