Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many hormones mediate their intracellular actions by triggering signal transduction pathways that alter the phosphorylation state of key regulatory proteins. Protein phosphorylation is a reversible process involving two classes of signaling enzymes: protein kinases, which catalyze the transfer of phosphate from ATP onto substrate proteins, and phosphoprotein phosphatases, which perform the dephosphorylation step. To insure tight control of hormonally initiated phosphorylation events, the activity of multifunctional kinases and phosphatases is precisely regulated and responds to fluctuations in diffusible second messengers such as Ca2+, phospholipid, and cAMP. Another mechanism that contributes to their regulation is to restrict the location of these enzymes to certain subcellular compartments. Subcellular targeting enhances the selectivity of serine/threonine phosphatases and kinases by favoring their accessibility to certain substrate proteins. Compartmentalization is achieved through a "targeting moiety," which is defined as that part of a phosphatase or kinase that directs the catalytic subunit to a certain subcellular environment. The targeting moiety restricts the location of a phosphatase or kinase through association with a "targeting locus." These are often structural membrane proteins, cytoskeletal components, or cellular organelles. Targeting subunits for the type I phosphatase and protein kinase C have been identified; however, the focus of this chapter centers around a family of anchoring proteins, called AKAPs, that localize the type II cAMP-dependent protein kinase (PKA). Structure-function analysis suggest that each anchoring protein binds to the RII dimer through a conserved amphipathic helix region and is tethered to specific subcellular sites via association of a targeting domain with structural proteins or cellular organelles. Peptides patterned after the amphipathic region have been used to probe the functional significance of PKA anchoring inside cells and have begun to be established by that disruption RII/AKAP interaction in vivo has concomitant effects on certain PKA-mediated phosphorylation events. In addition, multivalent binding proteins such as AKAP79 and AKAP250 have been characterized and appear to serve as platforms for the assembly of kinase/phosphatase signaling complexes. Collectively, these studies suggest that the AKAPs represent a growing family of regulatory proteins that provide a molecular architecture that organizes the intracellular location of a single or multiple multifunctional kinase.
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PMID:Anchoring and scaffold proteins for kinases and phosphatases. 923 61

Three proteins are functionally interlinked in the targeting of protein phosphorylation catalyzed by the C-subunit of PKA: PKA itself, AKAPs and NMT. Furthermore, in a variety of biological contexts, mechanisms exist whereby PKA and PKC are able to modulate the activity of one another. We have investigated the expression and subcellular distribution of these proteins in two models of mammary cell proliferation and differentiation--the normal rat mammary gland during pregnancy and lactation and human breast tissue before and after malignant transformation. Modulation of PKA does not acutely affect activity or sub-cellular distribution of PKC in mammary acini, nor does modulation of PKC acutely affect PKA activity or subcellular distribution. Therefore, the co-ordinate expression of these two protein kinases in normal and cancerous mammary epithelial cells and the greater basal activation level of them both accompanying increased mitogenic activity, which we have reported, does not result from short-term cross-talk between them. Although basal and total levels of PKA diminish in rodent mammary epithelial cells during the transition from proliferative to secretory functional mode, the level of expression of AKAPs increases. The expression of two apparently mammary-specific and mostly membrane-associated AKAPs is tightly linked to the onset and maintenance of differentiated function in rat mammary tissue. Paradoxically, the probable analogues of these two AKAPs in human mammary tissue are hyperexpressed when normal epithelial cells transform to a cancer phenotype--conventionally regarded as a process involving a degree of dedifferentiation. Mammary AKAP hyperexpression in breast cancers is accompanied by increases in the levels of total and basal PKA. One mechanism whereby NMT is targeted to membranes, via interaction with ribosomal proteins, has recently been elucidated. Our data support the contention that the localization of NMT is an important variable in the regulation of cellular proliferation, but they do not characterize the mechanisms whereby the differential targeting of NMT is achieved. As yet we lack a full tool-kit with which to examine NMT either to draw firm conclusions regarding the identity of particular isoforms found in particular sub-cellular locations or to define the relationships between these different molecular variants. However, it is technically possible to transfect cells with inducible NMT expression constructs engineered in such a way that the recombinant, catalytically competent, NMT that they encode is targeted either to membranes or to cytosol: an exploration of the effects of such transfections on cellular proliferation would afford a critical test of the mechanistic involvement of NMT in the control of mitogenesis.
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PMID:Expression of enzymes of covalent protein modification during regulated and dysregulated proliferation of mammary epithelial cells: PKA, PKC and NMT. 1047 Mar 73

The adhesive phenotype of neutrophils (PMN) depends largely on activating and deactivating intracellular signals regulating beta2 integrin avidity for ligand. Our hypothesis is that PKA is a negative regulator of beta2 integrin avidity. In this work, we examined the role of PKA in PMN alphaMbeta2 integrin activation. Elevation of cAMP inhibited alphaMbeta2 integrin-dependent adhesion of PMN to immune complexes (IC), but not PMA-induced adhesion. The PKA inhibitor KT5720 reversed the ability of cAMP to suppress adhesion to IC. Moreover, inhibition of PKA activity was sufficient to activate alphaMbeta2 integrin-dependent adhesion and increase beta2 integrin expression and binding of the monoclonal antibody CBRM1/5, which recognizes activated alphaMbeta2 specifically. However, PKA activity was necessary for sustained adhesion. Disruption of A kinase-anchoring, protein-PKA binding with a cell-permeant peptide derived from the AKAP Ht31 also activated adhesion. Unlike pharmacologic inhibition of PKA, AKAP peptide-induced adhesion was PKC dependent and did not affect beta2 integrin expression or CBRM1/5 binding. These data demonstrate that PKA appears to have a dual role in the mechanism regulating alphaMbeta2 integrin avidity and adhesion.
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PMID:Protein kinase A regulates beta2 integrin avidity in neutrophils. 1205 Jan 91

Activation of D1-like dopamine (DA) receptors reduces peak Na(+) current in hippocampal neurons voltage-dependent in a manner via phosphorylation of the alpha subunit. This modulation is dependent upon activation of cAMP-dependent protein kinase (PKA) and requires phosphorylation of serine 573 (S573) in the intracellular loop connecting homologous domains I and II (L(I-II)) by PKA anchored to A kinase anchoring protein-15 (AKAP-15). Activation of protein kinase C (PKC) also reduces peak Na(+) currents and enhances the strength of the PKA modulatory pathway. Here we probe the molecular mechanism responsible for the convergent effects of PKA and PKC on brain Na(v)1.2a channels. Analysis of the interaction of AKAP-15 with the intracellular loops of the Na(v)1.2a channel shows that it binds to L(I-II), thereby targeting PKA directly to its sites of phosphorylation on the Na(+) channel by specific protein-protein interactions. Mutagenesis and expression experiments indicate that reduction of peak Na(+) current by PKC requires S554 and S573 in L(I-II) in addition to S1506 in the inactivation gate. In addition, PKC-dependent phosphorylation of S576 in L(I-II) is necessary for enhancement of PKA modulation of brain Na(+) channels. When S576 is phosphorylated by PKC, the increase in modulation by PKA activation requires phosphorylation of S687 in L(I-II). Thus, the maximal modulation of these Na(+) channels by concurrent activation of PKA and PKC requires phosphorylation at four distinct sites in L(I-II): S554, S573, S576, and S687. This convergent regulation provides a novel mechanism by which information from multiple signaling pathways may be integrated at the cellular level in the hippocampus and throughout the central nervous system.
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PMID:Molecular mechanism of convergent regulation of brain Na(+) channels by protein kinase C and protein kinase A anchored to AKAP-15. 1235 52

We have used differential display to profile and compare the mRNAs expressed in the hippocampus of freely moving animals after the induction of long-term potentiation (LTP) at the perforant path-dentate gyrus synapse with control rats receiving low-frequency stimulation. We have combined this with in situ hybridization and have identified A-kinase anchoring protein of 150 kDa (AKAP-150) as a gene selectively up-regulated during the maintenance phase of LTP. AKAP-150 mRNA has a biphasic modulation in the dentate gyrus following the induction of LTP. The expression of AKAP-150 was 29% lower than stimulated controls 1 h after the induction of LTP. Its expression was enhanced 3 (50%), 6 (239%) and 12 h (210%) after induction, returning to control levels by 24 h postinduction. The NMDA receptor antagonist CPP blocked the tetanus-induced modulation of AKAP-150 expression. Interestingly, strong generalized stimulation produced by electroconvulsive shock did not increase the expression of AKAP-150. This implies that the AKAP-150 harbours a novel property of selective responsiveness to the stimulation patterns that trigger NMDA-dependent LTP in vivo. Its selective up-regulation during LTP and its identified functions as a scaffold for protein kinase A, protein kinase C, calmodulin, calcineurin and ionotropic glutamate receptors suggest that AKAP-150 encodes is an important effector protein in the expression of late LTP.
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PMID:LTP but not seizure is associated with up-regulation of AKAP-150. 1254 70

M-type (KCNQ2/3) potassium channels are suppressed by activation of G(q/11)-coupled receptors, thereby increasing neuronal excitability. We show here that rat KCNQ2 can bind directly to the multivalent A-kinase-anchoring protein AKAP150. Peptides that block AKAP150 binding to the KCNQ2 channel complex antagonize the muscarinic inhibition of the currents. A mutant form of AKAP150, AKAP(DeltaA), which is unable to bind protein kinase C (PKC), also attenuates the agonist-induced current suppression. Analysis of recombinant KCNQ2 channels suggests that targeting of PKC through association with AKAP150 is important for the inhibition. Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. Our data indicate that AKAP150-bound PKC participates in receptor-induced inhibition of the M-current.
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PMID:AKAP150 signaling complex promotes suppression of the M-current by muscarinic agonists. 1275 13

A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. The receptor-binding domain of the scaffold and the regulation of the receptor-scaffold association was revealed through mutagenesis and biochemical analyses. The AKAP domain found in other members of this superfamily is essential for the scaffold-receptor interactions. Gravin constructs lacking the AKAP domain displayed no binding to the receptor. Metabolic labeling studies in vivo demonstrate agonist-stimulated phosphorylation of gravin and enhanced gravin-receptor association. Analysis of the AKAP domain revealed two canonical PKA sites phosphorylated in response to elevated cAMP, blocked by PKA inhibitor, and essential for scaffold-receptor association and for resensitization of the receptor. The AKAP appears to provide the catalytic PKA activity responsible for phosphorylation of the scaffold in response to agonist activation of the receptor as well as for the association of the scaffold with the receptor, a step critical to receptor resensitization.
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PMID:Protein kinase A regulates AKAP250 (gravin) scaffold binding to the beta2-adrenergic receptor. 1465 15

In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase-mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation and immunofluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell.
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PMID:Kinase signaling cascades in the mitochondrion: a matter of life or death. 1558 66

The second messenger for closure of M/KCNQ potassium channels in post-ganglionic neurons and central neurons had remained as a 'mystery in the neuroscience field' for over 25 years. However, recently the details of the pathway leading from muscarinic acetylcholine receptor (mAChR)-stimulation to suppression of the M/KCNQ-current were discovered. A key molecule is A-kinase anchoring protein (AKAP; AKAP79 in human, or its rat homolog, AKAP150) which forms a trimeric complex with protein kinase C (PKC) and KCNQ channels. AKAP79 or 150 serves as an adapter that brings the anchored C-kinase to the substrate KCNQ channel to permit the rapid and 'definitive' phosphorylation of serine residues, resulting in avoidance of signal dispersion. Thus, these findings suggest that mAChR-induced short-term modulation (or memory) does occur within the already well-integrated molecular complex, without accompanying Hebbian synapse plasticity. However, before this identity is confirmed, many other modulators which affect M-currents remain to be addressed as intriguing issues.
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PMID:Protein kinase C bound with A-kinase anchoring protein is involved in muscarinic receptor-activated modulation of M-type KCNQ potassium channels. 1571 Apr 86

Specificity in cell signalling can be influenced by the targeting of different enzyme combinations to substrates. The A-kinase anchoring protein AKAP79/150 is a multivalent scaffolding protein that coordinates the subcellular localization of second-messenger-regulated enzymes, such as protein kinase A, protein kinase C and protein phosphatase 2B. We developed a new strategy that combines RNA interference of the endogenous protein with a protocol that selects cells that have been rescued with AKAP79/150 forms that are unable to anchor selected enzymes. Using this approach, we show that AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels. Utilization of distinct enzyme combinations in this manner provides a means to expand the repertoire of cellular events that the same AKAP modulates.
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PMID:Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. 1638 33


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