Alternative titles; symbols
HGNC Approved Gene Symbol: PRKCA
Cytogenetic location: 17q24.2 Genomic coordinates (GRCh38): 17:66,302,613-66,810,743 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q24.2 | Pituitary tumor, invasive | 3 |
Protein kinase C (PKC) is the major phorbol ester receptor. Parker et al. (1986) purified this protein from bovine brain and through the use of oligonucleotide probes based on partial amino acid sequence, derived cDNA clones from bovine cDNA libraries. Thus, the complete amino acid sequence of bovine protein kinase C was determined, revealing a domain structure. Activation of PKC by calcium ions and the second messenger diacylglycerol is thought to play a central role in the induction of cellular responses to a variety of ligand-receptor systems and in the regulation of cellular responsiveness to external stimuli.
Finkenzeller et al. (1990) reported the nucleotide sequence of cDNA clones of the PKCA gene.
Coussens et al. (1986) defined a new family of PKC-related genes in bovine, human and rat genomes. Three of these, termed alpha, beta (PRKCB1; 176970), and gamma (PRKCG; 176980), are highly homologous. From Southern blot analysis Coussens et al. (1986) concluded that even more PKC genes may exist.
Ekinci and Shea (1999) stated that PKC-alpha is reversibly activated at the plasma membrane by transient generation of diacylglycerol (DAG), coupled with the release of Ca(2+) from intracellular stores, following receptor-mediated hydrolysis of inositol phospholipids. PKC-alpha is also irreversibly activated by calpain (see 114220)-mediated cleavage of its regulatory and catalytic subunits, resulting in a cofactor-independent, free PKC-alpha catalytic subunit termed PKM-alpha. Ekinci and Shea (1999) found that activation of PKC-alpha in human neuroblastoma cells by either the phorbol ester TPA or by ionophore-mediated calcium mobilization, which experimentally correspond to DAG-mediated and calpain-mediated activation, respectively, resulted in increased phosphorylation of the microtubule-associated protein tau (MAPT; 157140). Activation of PKC-alpha by calcium mobilization, but not TPA, generated PKM-alpha and resulted in calpain-dependent release of PKM-alpha from the plasma membrane. The TPA-mediated increase in tau phosphorylation was blocked by cotreatment with an MAP2K (see 176872) inhibitor, but ionophore-mediated tau phosphorylation was not.
Lorenz et al. (2003) demonstrated that the RAF kinase inhibitor protein (RKIP; 604591) is a physiologic inhibitor of GRK2 (109635). After stimulation of G protein-coupled receptors, RKIP dissociates from its known target, RAF1 (164760), to associate with GRK2 and block its activity. This switch is triggered by a PKC-dependent phosphorylation of RKIP on serine-153. Lorenz et al. (2003) concluded that their data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from RAF1 and by blocking receptor internalization. A physiologic role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signaling and contractile activity.
Birnbaum et al. (2004) tested the influence of PKC intracellular signaling on prefrontal cortical cognitive function in rats and monkeys and showed that high levels of PKC activity in prefrontal cortex, as seen for example during stress exposure, markedly impaired behavioral and electrophysiologic measures of working memory. Birnbaum et al. (2004) concluded that excessive PKC activation can disrupt prefrontal cortical regulation of behavior and thought, possibly contributing to signs of prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder.
Hermoso et al. (2004) showed that efficient volume regulation in response to hypotonicity in HeLa cells required the kinase activity of PKC-alpha. The response to hypotonicity involved accumulation of PKC-alpha at the plasma membrane.
Bivona et al. (2006) found that the subcellular localization and function of Kras (see KRAS2; 190070) in mammalian cells was modulated by Pkc. Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl (BCL2L1; 600039). Phosphorylated Kras required Bclxl for induction of apoptosis.
Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (103070), PRKACG (176893), CAMK2G (602123), GRIN2A (138253), GRIN2B (138252), GRM3 (601115), and PRKCA genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function.
Robles et al. (2010) analyzed mouse protein complexes containing BMAL1 (602550) to gain insight into the mechanisms of circadian feedback. Receptors for RACK1 (176981) and PKC-alpha were recruited in a circadian manner into a nuclear BMAL1 complex during the negative feedback phase of the cycle. Overexpression of RACK1 and PKC-alpha suppressed CLOCK (601851)-BMAL1 transcriptional activity, and RACK1 stimulated phosphorylation of BMAL1 by PKC-alpha in vitro. Depletion of endogenous RACK1 or PKC-alpha from fibroblasts shortened the circadian period, demonstrating that both molecules function in the clock oscillatory mechanism. Robles et al. (2010) concluded that the classical PKC signaling pathway is not limited to relaying external stimuli but is rhythmically activated by internal processes, forming an integral part of the circadian feedback loop.
By Southern analysis of hybrid cell DNA and by in situ hybridization, Coussens et al. (1986) found that the PRKCA gene maps to 17q22-q24, and that the PRKCB1 and PRKCG genes are situated in the 16p12-q11.1 and 19q13.2-q13.4 segments, respectively.
Latos-Bielenska et al. (1991) refined the assignment of PRKCA1 to 17q22-q23.2 by study of a translocation t(2;17) by in situ hybridization.
In family linkage studies using the CEPH panel of DNAs and RFLP markers, Summar et al. (1989) estimated the most likely interval between PKCA and GH1 (139250) and PKCA and COL1A1 (120150) to be 0.03 and 0.11, respectively. The theta value calculated for GH1 versus COL1A1 was 0.11. They suggested that the most likely gene order is centromere--COL1A1--PKCA--GH1. On the other hand, Jones et al. (1991) placed PKCA just distal to GH1 by the study of chromosome 17 fragment-containing hybrids.
In a primary melanoma cell line, Linnenbach et al. (1988) found a tumor-specific deletion within the PKCA gene; the deletion was not detectable cytogenetically.
In 4 invasive pituitary tumors, Alvaro et al. (1993) identified a point mutation in the PKCA gene.
For discussion of an association between variation in the PRKCA gene and body mass index (BMI) and asthma, see BMIQ15 (612967) and susceptibility to asthma (600807), respectively.
The L7-PKCi transgenic mouse developed by De Zeeuw et al. (1998) has a Purkinje cell-specific promoter to drive the expression of a peptide that inhibits protein kinase C. The mouse demonstrates impaired parallel fiber long-term depression (LTD) in Purkinje cells in vitro and in vivo but has no motor performance or excitability defects (De Zeeuw et al., 1998; Goossens et al., 2001; Gao et al., 2003). Koekkoek et al. (2003) demonstrated that the protein kinase C-dependent LTD in Purkinje cells of this mouse model is necessary for the learning-dependent timing of Pavlovian-conditioned eyeblink responses.
Braz et al. (2004) identified PKC-alpha as a fundamental regulator of cardiac contractility and Ca(2+) handling in myocytes. Hearts of Prkca-deficient mice were hypercontractile, whereas those of transgenic mice overexpressing Prkca were hypocontractile. Adenoviral gene transfer of dominant-negative or wildtype PKC-alpha into cardiac myocytes enhanced or reduced contractility, respectively. Modulation of PKC-alpha activity affected dephosphorylation of the sarcoplasmic reticulum Ca(2+) ATPase-2 pump inhibitory protein phospholamban (PLN; 172405) and altered sarcoplasmic reticulum Ca(2+) loading and the Ca(2+) transient. PKC-alpha was found to phosphorylate protein phosphatase inhibitor-1 directly, altering the activity of protein phosphatase-1 (PP1; see 176875), which might account for the effects of PKC-alpha on PLN phosphorylation. Hypercontractility caused by Prkca deletion protected against heart failure induced by pressure overload and against dilated cardiomyopathy induced by deleting the Csrp3 gene (600824). Deletion of Prkca also rescued cardiomyopathy associated with overexpression of PP1. Braz et al. (2004) concluded that 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.
Rochefort et al. (2011) sought to determine the role of cerebellar PKC-dependent plasticity in spatial navigation by recording the activity of hippocampal place cells in transgenic L7PKCI mice with selective disruption of PKC-dependent plasticity at parallel fiber-Purkinje cell synapses. Place cell properties were exclusively impaired when L7PKCI mice had to rely on self-motion cues. The behavioral consequence of such a deficit was evidenced by selectively impaired navigation capabilities during a path integration task. Rochefort et al. (2011) concluded that cerebellar PKC-dependent mechanisms are involved in processing self-motion signals essential to the shaping of hippocampal spatial representation.
Alvaro, V., Levy, L., Dubray, C., Roche, A., Peillon, F., Querat, B., Joubert, D. Invasive human pituitary tumors express a point-mutated alpha-protein kinase-C. J. Clin. Endocr. 77: 1125-1129, 1993. [PubMed: 8077302] [Full Text: https://doi.org/10.1210/jcem.77.5.8077302]
Birnbaum, S. G., Yuan, P. X., Wang, M., Vijayraghavan, S., Bloom, A. K., Davis, D. J., Gobeske, K. T., Sweatt, J. D., Manji, H. K., Arnsten, A. F. T. Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306: 882-884, 2004. [PubMed: 15514161] [Full Text: https://doi.org/10.1126/science.1100021]
Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Miura, J., Wiener, H. H., Wright, L., Saba, S. G., Yim, D., Fein, A., Perez de Castro, I., Li, C., Thompson, C. B., Cox, A. D., Philips, M. R. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-X(L) on mitochondria and induces apoptosis. Molec. Cell 21: 481-493, 2006. [PubMed: 16483930] [Full Text: https://doi.org/10.1016/j.molcel.2006.01.012]
Braz, J. C., Gregory, K., Pathak, A., Zhao, W., Sahin, B., Klevitsky, R., Kimball, T. F., Lorenz, J. N., Nairn, A. C., Liggett, S. B., Bodi, I., Wang, S., and 9 others. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nature Med. 10: 248-254, 2004. [PubMed: 14966518] [Full Text: https://doi.org/10.1038/nm1000]
Coussens, L., Parker, P. J., Rhee, L., Yang-Feng, T. L., Chen, E., Waterfield, M. D., Francke, U., Ullrich, A. Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways. Science 233: 859-866, 1986. [PubMed: 3755548] [Full Text: https://doi.org/10.1126/science.3755548]
de Quervain, D. J.-F., Papassotiropoulos, A. Identification of a genetic cluster influencing memory performance and hippocampal activity in humans. Proc. Nat. Acad. Sci. 103: 4270-4274, 2006. [PubMed: 16537520] [Full Text: https://doi.org/10.1073/pnas.0510212103]
De Zeeuw, C. I., Hansel, C., Bian, F., Koekkoek, S. K. E., van Alphen, A. M., Linden, D. J., Oberdick, J. Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron 20: 495-508, 1998. [PubMed: 9539124] [Full Text: https://doi.org/10.1016/s0896-6273(00)80990-3]
Ekinci, F. J., Shea, T. B. Free PKC catalytic subunits (PKM) phosphorylate tau via a pathway distinct from that utilized by intact PKC. Brain Res. 850: 207-216, 1999. [PubMed: 10629766] [Full Text: https://doi.org/10.1016/s0006-8993(99)02146-0]
Finkenzeller, G., Marme, D., Hug, H. Sequence of human protein kinase C alpha. Nucleic Acids Res. 18: 2183 only, 1990. [PubMed: 2336401] [Full Text: https://doi.org/10.1093/nar/18.8.2183]
Gao, W., Dunbar, R. L., Chen, G., Reinert, K. C., Oberdick, J., Ebner, T. J. Optical imaging of long-term depression in the mouse cerebellar cortex in vivo. J. Neurosci. 23: 1859-1866, 2003. Note: Erratum: J. Neurosci. 23: 4791 only, 2003. [PubMed: 12629190] [Full Text: https://doi.org/10.1523/JNEUROSCI.23-05-01859.2003]
Goossens, J., Daniel, H., Rancillac, A., van der Steen, J., Oberdick, J., Crepel, F., De Zeeuw, C. I., Frens, M. A. Expression of protein kinase C inhibitor blocks cerebellar long-term depression without affecting Purkinje cell excitability in alert mice. J. Neurosci. 21: 5813-5823, 2001. [PubMed: 11466453] [Full Text: https://doi.org/10.1523/JNEUROSCI.21-15-05813.2001]
Hermoso, M., Olivero, P., Torres, R., Riveros, A., Quest, A. F. G., Stutzin, A. Cell volume regulation in response to hypotonicity is impaired in HeLa cells expressing a protein kinase C-alpha mutant lacking kinase activity. J. Biol. Chem. 279: 17681-17689, 2004. [PubMed: 14960580] [Full Text: https://doi.org/10.1074/jbc.M304506200]
Jones, K. W., Shapero, M. H., Chevrette, M., Fournier, R. E. K. Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A. Cell 66: 861-872, 1991. [PubMed: 1889088] [Full Text: https://doi.org/10.1016/0092-8674(91)90433-y]
Koekkoek, S. K. E., Hulscher, H. C., Dortland, B. R., Hensbroek, R. A., Elgersma, Y., Ruigrok, T. J. H., De Zeeuw, C. I. Cerebellar LTD and learning-dependent timing of conditioned eyelid responses. Science 301: 1736-1739, 2003. [PubMed: 14500987] [Full Text: https://doi.org/10.1126/science.1088383]
Latos-Bielenska, A., Klett, C., Just, W., Hameister, H. Refinement of localization of the human genes for myeloperoxidase (MPO), protein kinase C, alpha polypeptide, PRKCA, and the DNA fragment D17S21 on chromosome 17q. Hereditas 115: 69-72, 1991. [PubMed: 1663499] [Full Text: https://doi.org/10.1111/j.1601-5223.1991.tb00348.x]
Linnenbach, A. J., Huebner, K., Reddy, E. P., Herlyn, M., Parmiter, A. H., Nowell, P. C., Koprowski, H. Structural alteration in the MYB protooncogene and deletion within the gene encoding alpha-type protein kinase C in human melanoma cell lines. Proc. Nat. Acad. Sci. 85: 74-78, 1988. [PubMed: 2829178] [Full Text: https://doi.org/10.1073/pnas.85.1.74]
Lorenz, K., Lohse, M. J., Quitterer, U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426: 574-579, 2003. [PubMed: 14654844] [Full Text: https://doi.org/10.1038/nature02158]
Parker, P. J., Coussens, L., Totty, N., Rhee, L., Young, S., Chen, E., Stabel, S., Waterfield, M. D., Ullrich, A. The complete primary structure of protein kinase C--the major phorbol ester receptor. Science 233: 853-859, 1986. [PubMed: 3755547] [Full Text: https://doi.org/10.1126/science.3755547]
Robles, M. S., Boyault, C., Knutti, D., Padmanabhan, K., Weitz, C. J. Identification of RACK1 and protein kinase C-alpha as integral components of the mammalian circadian clock. Science 327: 463-466, 2010. [PubMed: 20093473] [Full Text: https://doi.org/10.1126/science.1180067]
Rochefort, C., Arabo, A., Andre, M., Poucet, B., Save, E., Rondi-Reig, L. Cerebellum shapes hippocampal spatial code. Science 334: 385-389, 2011. [PubMed: 22021859] [Full Text: https://doi.org/10.1126/science.1207403]
Summar, M. L., Phillips, J. A., III, Krishnamani, M. R. S., Keefer, J., Trofatter, J., Schwartz, R. C., Tsipouras, P., Willard, H., Ullrich, A. Protein kinase C: a new linkage marker for growth hormone and for COL1A1. Genomics 5: 163-165, 1989. [PubMed: 2570026] [Full Text: https://doi.org/10.1016/0888-7543(89)90104-3]