Disease relevance of Prkca

• Hyperglycemia increased diacylglycerol (DAG) level in cultured mesangial cells exposed to high concentrations of glucose and activated PKC alpha and beta1 isoforms in the renal glomeruli of diabetic rats [1].
• Similar results were obtained by transfection of dominant-negative PKC-alpha using adenovirus vector [2].
• Thus PKC-alpha is necessary for certain aspects of PMA-induced NRVM hypertrophy [3].
• Western blot analysis revealed that the total amounts of PKC-alpha (-26.0% of control) and -gamma (-32.7% of control) were decreased significantly at the end of hypoxia, which was followed by the reduction of that of PKC-beta II (-23.7% of control at 7 days after hypoxia) [4].
• These results suggest that inactivation and the suppression of PKC-alpha gene transcription might be involved in modulating hepatic failure during sepsis [5].

High impact information on Prkca

• Here we identify PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes [6].
• Thus, PKC-alpha functions as a nodal integrator of cardiac contractility by sensing intracellular Ca(2+) and signal transduction events, which can profoundly affect propensity toward heart failure [6].
• Adenoviral gene transfer of dominant-negative or wild-type PKC-alpha into cardiac myocytes enhances or reduces contractility, respectively [6].
• Here, we report that overexpression of the reported mutant PKC alpha complementary DNA in three fibroblast cell lines, including BALB/c 3T3, does not enable these cells to grow in soft agar or nude mice [7].
• These results fail to confirm the previous study and indicate that overexpression of either the wild-type or the reported mutant form of PKC alpha does not transform rodent fibroblasts [7].

Chemical compound and disease context of Prkca

• To determine whether bile acids might activate PKC isozymes more directly, their effects on PKC alpha and delta purified from baculovirus expression systems were examined in phosphatidylserine/phosphatidylcholine/Triton X-100 (PS/PC/TX) mixed micelles [8].
• The increased expression of PKC alpha protein in diabetic rats was reversed by insulin but not by phlorizin, suggesting that it did not result from hyperglycemia [9].
• Chloroquine activates p38 MAPK and stimulates PKC-alpha and -delta translocation from the cytosol to the membrane in C6 glioma cells [10].
• We have previously demonstrated that levels of PKC alpha mRNA, protein, and enzyme activity in B16 melanoma cells can be modulated by retinoic acid [11].
• A single injection of cationic liposome ribozyme complexes into glioma tumors inhibited tumor growth, demonstrating both the efficacy of the ribozyme and a major role of PKC alpha in tumor growth [12].

Biological context of Prkca

• Our laboratory has previously demonstrated that 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) rapidly stimulated polyphosphoinositide (PI) hydrolysis, raised intracellular Ca2+, and activated two Ca2+-dependent protein kinase C (PKC) isoforms, PKC-alpha and -betaII in the rat large intestine [13].
• By trypsin treatment of PKC alpha, a 32-kDa lipid binding regulatory and a 50-kDa catalytic domain were generated that were subsequently completely separated by gel filtration in the presence of Triton X-100/phosphatidylserine mixed micelles [14].
• In this study, we define the kinetics of inhibition by staurosporine of a catalytic fragment of rat brain PKC-gamma and of a catalytic fragment generated from a rat brain PKC-alpha/PKC-beta mixture [15].
• PKC alpha mediates maternal touch regulation of growth-related gene expression in infant rats [16].
• Down-regulation of PKC-alpha and -delta isoenzymes by 8 h phorbol ester treatment still resulted in full PLD activation [17].

Anatomical context of Prkca

• PKC-alpha was found only in beta-cells, PKC-gamma in alpha-cells, and PKC-epsilon in delta-cells and vascular walls [18].
• PC-PLD activation was also accompanied by increases in total DAG production and increases in the translocation of both PKC enzyme activity and DAG-sensitive PKC-alpha, -beta, -delta, and -epsilon from the cytosol to the membrane fraction [19].
• Effects of phorbol esters on PKC-alpha redistribution to the plasma membrane, however, were much greater than those of insulin [20].
• Immunoreactivity of PKC-alpha, -beta, and -epsilon also indicated that their levels are diminished in fa/fa soleus muscle by 70-90% [21].
• At least three different phorbol ester-sensitive PKC isoenzymes are expressed in neonatal rat ventricular myocytes (NRVMs): PKC-alpha, -delta, and -epsilon [3].

Associations of Prkca with chemical compounds

• PKC alpha was found to separate into two peaks on hydroxylapatite chromatography [22].
• Furthermore, it is shown that PKC alpha forms dimers via inter-molecular interactions between the C1 and C2 domains of two neighboring molecules [23].
• Taken together, PKC-alpha is activated when cells are depolarized by a high concentration of potassium or glucose [2].
• ET-1 and PHE, to much lesser extent, produced a rapid (0-5 min) translocation of PKC- immunoreactivity from the cytosol to the membrane fraction, whereas no intracellular redistribution of PKC-alpha, -delta and -xi immunoreactivities was observed [24].
• PKC alpha overexpression in cardiomyocytes caused marked repression of triiodothyronine (T3)-responsive genes, alpha-myosin heavy chain, and the sarcoplasmic reticulum calcium-activated adenosinetriphosphatase SERCA2 [25].

Physical interactions of Prkca

• The PKC-alpha binding domain of rPLD1 was localized to its N-terminus [26].
• Furthermore, it was found that alpha C1A-C1B bound to a peptide containing the C2 domain of PKC alpha [23].
• We speculated that the reason for changes after TPA treatment was the interactions with activated PKC alpha, which provoked syndecan-4/PKC alpha complex translocation to integrins [27].

Enzymatic interactions of Prkca

• The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890 [28].

Regulatory relationships of Prkca

• These results suggest that a covalent bridge between vicinal thiol groups of cell surface proteins induced by PAO potentiates PLD activation and that PAO-induced PLD activation is regulated by Ca2+ and PKC alpha and/or beta isozymes [29].
• These results suggest that in the antigen-mediated PLD pathway PKC may be implicated but not play such a great role as PMA-stimulated pathway which is mediated through PKC alpha or beta [30].
• PMA treatment or PKC-alpha overexpression also inhibited the tyrosine phosphorylation of IRS-1 [31].
• Insulin inhibits secretin-induced ductal secretion by activation of PKC alpha and inhibition of PKA activity [32].
• Insulin-like growth factor-1 also induced nuclear translocation of endogenous PKC-alpha [3].

Other interactions of Prkca

• Peak I reacted exclusively with antisera to PKC gamma, peak II with PKC beta I and -beta II, and peak III with PKC alpha [33].
• PKC alpha, -beta and -gamma isoenzymes separated by hydroxylapatite chromatography all cross-reacted with anti-PKC zeta [22].
• Interestingly, PLD1 was associated with PKC-alpha or beta II, and its association gradually increased as NGF-induced neuronal differentiation progressed [34].
• These results suggest that PKC alpha activity as well as p38MAPK activity is associated with TNF alpha induction in LPS-stimulated microglia [35].
• Thus, in GH4C1 cells, Ca2(+)-independent nPKC epsilon may play a crucial role distinct from that mediated by Ca2(+)-dependent PKC alpha and beta II in a cellular response elicited by both TRH and phorbol esters [36].

Analytical, diagnostic and therapeutic context of Prkca

• Confocal microscopy with standard immunostaining techniques confirmed earlier observations that colchicine disruption of microtubules blocked PKC-alpha localization in the perinuclear region of the cell caused by phorbol 12,13-dibutyrate (PDBu; 10-6M) [37].
• Western blot analysis revealed decreases in the levels of cytosolic PKC alpha and PKC beta in the injured cortex after brain injury [38].
• A novel Ca2(+)-independent PKC, nPKC epsilon, was identified together with two conventional Ca2(+)-dependent PKCs, PKC alpha and beta II by analysis of kinase and phorbol ester-binding activities, immunoblotting using isozyme-specific antibodies, and Northern blotting [36].
• PKC-alpha is present primarily in bipolar cells of rat, fish and rabbit retinas and was not detected by immunohistochemistry or blotting experiments in the frog retina [39].
• Polymerase chain reaction (PCR) and Western blot analysis revealed the presence of PKC alpha, beta I and beta II isoenzymes in the rat pituitary gland but not of PKC gamma isoenzymes [40].

References