ReviewProtein kinase C as a stress sensor
Introduction
The protein kinase C (PKC) family of proteins is part of the larger ABC protein kinases which includes Protein Kinase A (PKA), Protein Kinase B (PKB, synonymous to Akt), and Protein Kinase C (PKC) [1], [2], [3]. All members of this superfamily have an N-terminal regulatory region and a conserved C-terminal kinase core that contains two conserved phosphorylation sites. These sites are known as the turn motif and hydrophobic motif. The regulatory regions of ABC kinases have two functions. One is to bind to the plasma membrane or other cellular targets, and the other is to inhibit the active site of the enzyme. The C-terminal region functions as the substrate binding site and phosphor-acceptor/donor site.
All ABC kinases contain an activation loop threonine that must be phosphorylated by upstream Phosphoinositide Dependent Kinase-1 (PDK-1), except protein kinase A (PKA) which is recognized by PDK-1, in vitro, but does not require PDK-1 activity in vivo. PDK-1 is constantly active, but, it's downstream substrates must be in an open conformation in order to become targets. For example, when the pleckstrin homology (PH) domain of protein kinase B (PKB) encounters Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), this opens the conformation, by disassociation of the PH domain, with the kinase core, revealing the activation loop. Once activated, PKB remains in this state. In contrast, PKCs are phosphorylated at the activation loop, but this only primes them. They still must interact with secondary messengers or other signals before becoming activated.
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Biochemical features
There are at least 10 isoforms of PKC that are divided into 3 groups related through their primary structure [3]. In general, PKCs contain a regulatory domain, with a pseudo substrate region, as well as the elements necessary to respond to second messengers (Fig. 1). The N-terminal regulatory domain is followed by a hinge region and the kinase core which contains the substrate and ATP binding sites in the C-terminus of PKC. PKCs, once processed in the cell by priming phosphorylation events by
PKCε in the heart
PKCε has been implicated as a major factor in the phenomena of cardiac preconditioning [38]. Under hypoxic conditions PKCε translocation to Cx43 and to mitochondria and subsequent protection from ischemia are dependent upon the presence of increased mitochondrial reactive oxygen species (ROS). The requirement for PKCε was confirmed using the PKCε null mouse hearts which do not develop tolerance to antimycinA-induced ischemia [39].
Cardiac preconditioning, which has been demonstrated in many
Conclusions
Both PKCγ and PKCε have open and easily activated C1 domains which allow them to become activated by oxidative signals and ROS, without a DAG or calcium signal. These PKC isoforms play a key role in the control of both mitochondria and gap junctions during ischemic stress. This stress control appears to involve, mainly, PKCε in heart, but the additional PKCγ in neural tissues. It is not certain if both PKCs control the Cx43 gap junction protein. However, the use of the available knockout models
Acknowledgements
This review was made possible by NIH grant number P20-RR016475 (to D. Madgwick) from the INBRE Program of the National Center for Research Resources, and NIH grant number RO1-EY13421 (to D. Takemoto).
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