Alternative titles; symbols
HGNC Approved Gene Symbol: PRKCE
Cytogenetic location: 2p21 Genomic coordinates (GRCh38): 2:45,651,279-46,187,990 (from NCBI)
Basta et al. (1992) isolated cDNA corresponding to the epsilon form of protein kinase C. At the amino acid level, the deduced human epsilon sequence showed 98 to 99% identity with the mouse, rat, and rabbit sequences.
Csukai et al. (1997) used the V1 region of PRKCE to clone a PRKCE-selective RACK (see RACK1; 176981), which they identified as Copb2 (606990), from rat. Immunofluorescence microscopy and immunoprecipitation analysis demonstrated colocalization of Copb2 with activated PRKCE in cardiac myocytes and that PRKCE binds to Golgi membranes in a Copb2-dependent manner.
As part of an approach to tumor gene discovery, Chen et al. (1998) assigned the PRKCE gene to chromosome 2p21 and identified it as a candidate for thyroid tumorigenesis.
VR1 (602076) and native VRs are nonselective cation channels directly activated by harmful heat, extracellular protons, and vanilloid compounds. VR1 is also expressed in nonsensory tissue and may mediate inflammatory rather than acute thermal pain. Premkumar and Ahern (2000) showed that activation of PKC-epsilon induces VR1 channel activity at room temperature in the absence of any other agonist. They also observed this effect in native VRs from sensory neurons, and phorbol esters induced a vanilloid-sensitive calcium rise in these cells. Moreover, the proinflammatory peptide bradykinin, and the putative endogenous ligand anandamide, induced and enhanced VR activity, respectively, in a PKC-dependent manner. These results suggested that PKC may link a range of stimuli to the activation of VRs.
Epidemiologic studies indicated beneficial effects of moderate ethanol consumption in ischemic heart disease. Most studies, however, focused on the effect of long-term consumption of ethanol. On the other hand, Chen et al. (1999) determined whether brief exposure to ethanol immediately before ischemia also produces cardioprotection. In addition, because protein kinase C has been shown to mediate protection of the heart from ischemia, they determined the role of specific PKC isozymes in ethanol-induced protection. They demonstrated that (i) brief exposure of isolated adult rat cardiac myocytes to 10-50 mM ethanol protected against damage induced by prolonged ischemia; (ii) an isozyme-sensitive PKC-epsilon inhibitor inhibited the cardioprotective effect of acute ethanol exposure; (iii) protection of isolated intact adult rat heart also occurred after incubation with 10 mM ethanol 20 minutes before global ischemia; and (iv) ethanol-induced cardioprotection depended on PKC activation because it was blocked by 2 PKC inhibitors. Consumption of 1 to 2 alcoholic beverages in humans leads to blood alcohol levels of approximately 10 mM. Therefore, this work demonstrated that exposure to physiologically attainable ethanol levels minutes before ischemia provides cardioprotection that is mediated by direct activation of PKC-epsilon in cardiac myocytes. They suggested that studies should be done examining the protection induced by ethanol exposure in humans immediately before scheduled ischemia, such as that occurring during angioplasty and in cardiac surgery. Identification of the role of PKC-epsilon in the cardioprotective effect of ethanol may result in development of a PKC-epsilon agonist that mimics the ethanol effect and provides protection against ischemic injury without the detrimental medical and social effects of drinking.
Using binding and immunoprecipitation assays on adult rat cortical tissue, Maeno-Hikichi et al. (2003) showed that the enigma-like LIM domain protein (ENH; 605904) interacts specifically with PKC-epsilon and the C terminus of the N-type calcium channel alpha-1B subunit (CACNA1B; 601012) to form a macromolecular complex. Functional studies in Xenopus oocytes indicated that expression of ENH resulted in increased rapid and specific modulation of N-type calcium channels by PKCE. The authors concluded that through interactions with a common adaptor protein, the formation of a kinase-substrate complex is the molecular basis for the specificity and efficiency of cellular signaling.
Chen et al. (1998) reported a general approach that translates comparative genome hybridization (CGH) data into higher-resolution genomic-clone data that are then used to define the genes located in aneuploid regions. They used CGH to study 33 thyroid tumor DNAs and 2 tumor cell line DNAs. The results revealed amplification of 2p21 with less intense amplification at other sites. To define the 2p21 region amplified, a dense array of 373 fluorescence in situ hybridization (FISH)-mapped chromosome 2 bacterial artificial chromosomes (BACs) was constructed, and 87 of these were hybridized to a tumor cell line. Four BACs carried genomic DNA that was amplified in these cells. The maximum amplified region was narrowed to 3 to 6 Mb by multicolor FISH with the flanking BACs, and the minimum amplicon size was defined by a contig of 420 kb. Sequence analysis of an amplified BAC revealed a fragment of the PRKCE gene, which was then shown to be amplified and rearranged in tumor cells.
Chen et al. (1998) found amplification of the 2p21 locus in 28% of thyroid neoplasms and in the WRO thyroid carcinoma cell line. By positional cloning, Knauf et al. (1999) identified a rearrangement and amplification of the PRKCE gene in WRO cells. This resulted in the overexpression of a chimeric/truncated PRKCE mRNA, coding for N-terminal amino acids 1-116 of the isozyme fused to an unrelated sequence. Cells expressing the truncated enzyme were resistant to apoptosis. These findings pointed to a role for the PRKCE gene in apoptosis signaling pathways in thyroid cells and indicated that a naturally occurring PRKCE mutant that functions as a dominant negative can block cell death triggered by a variety of stimuli.
Ding et al. (2002) determined that expression of PRKCE is upregulated in chemotherapy-resistant non-small cell lung cancer cell lines. The chemosensitive phenotype of a small cell lung cancer cell line was associated with transcriptional inactivation of PRKCE. By biochemical assay, Ding et al. (2002) determined that expression of PRKCE inhibits chemotherapy-induced caspase-3 (600636) activation and apoptosis, thereby leading to cell survival. Downregulation of PRKCE expression by antisense cDNA in a chemotherapy-resistant cell line resulted in increased sensitivity.
Baines et al. (2003) stated that activation of Prkce is cardioprotective in some animal models of myocardial ischemia/reperfusion injury and that cardioprotective stimuli can induce translocation of Prkce to mitochondria. Using coimmunoprecipitation and in vitro pull-down assays of mouse cardiac mitochondria, they demonstrated that Prkce interacted with components of the mitochondrial permeability transition pore, including Vdac (see VDAC1; 604492). Furthermore, Prkce phosphorylated Vdac1 in vitro. Transgenic activation of Prkce in mice enhanced signaling complex formation between Prkce and the pore, concomitant with inhibition of Ca(2+)-induced pore opening. Administration of the pore opener atractyloside to transgenic mice attenuated the cardioprotective effect of activated Prkce against ischemia/reperfusion injury.
For discussion of a possible association between SHORT syndrome (see 269880) and variation in the PRKCE gene, see 176975.0001.
Using targeted disruption of exon 1 of the Prkce gene, Castrillo et al. (2001) generated mice deficient in Prkce. These mice had normal life expectancy and immune system markers, but they were smaller in weight and had reduced fertility due to frequent, copious gram-negative bacteria infections in the uterus. Macrophages from Prkce -/- mice generated dramatically reduced levels of nitric oxide, tumor necrosis factor-alpha (TNFA; 191160), and interleukin-1-beta (IL1B; 147720) in response to lipopolysaccharide (LPS) and gamma-interferon (IFNG; 147570). Western and Northern blot analyses showed reduced nitric oxide synthase-2 (NOS2; 163730) responses as well as reduced Ikk (603258) and nuclear factor kappa-B (NFKB; 164011) activation after exposure to LPS. In response to intravenous gram-negative or gram-positive bacteria infections, Prkce-deficient mice demonstrated a significantly decreased period of survival. Castrillo et al. (2001) concluded that PRKCE is critically involved at an early stage in LPS-mediated signaling in activated macrophages.
Hodge et al. (2002) found that Prkce-null mice showed reduced anxiety-like behavior, which was accompanied by reduced levels of stress hormones, including adrenocorticotrophic hormone. Treatment of Prkce-null mice with a GABA-alpha receptor (see 137160) antagonist restored corticosterone levels and anxiety-like behavior.
Littler et al. (2003) found that Prkce-null mice showed decreased hypoxic pulmonary vasoconstriction. They also found increased expression of a voltage-gated potassium channel, Kv3.1b (see 176258), in pulmonary artery smooth muscle cells of Prkce-null mice. Littler et al. (2003) hypothesized that the absence of Prkce permitted increased Kv3.1b expression, which contributed to the decreased vasoconstriction response.
Choi et al. (2006) found that doubly transgenic mice expressing an Alzheimer disease (104300)-associated APP (104760) mutation and overexpressing PRKCE had decreased amyloid plaques, plaque-associated neuritic dystrophy, and reactive astrocytosis compared to mice only expressing the APP mutation. There was no evidence for altered APP cleavage in the doubly transgenic mice; instead, overexpression of PRKCE increased the activity of endothelin-converting enzyme (ECE1; 600423), which degrades beta-amyloid.
This variant has been classified as a variant of unknown significance because its contribution to Short syndrome (see 269880) has not been confirmed.
By whole-exome sequencing in a 13-year-old girl who exhibited features consistent with SHORT syndrome but who was negative for mutation in the PIK3R1 gene (171833), Alcantara et al. (2017) identified heterozygosity for a de novo c.1795G-A transition (c.1795G-A, NM_005400.2) in exon 13 of the PRKCE gene, resulting in a glu599-to-lys (E599K) substitution at a highly conserved residue within the kinase domain. The mutation was not present in her unaffected parents or in the ExAC, gnomAD, or ClinVar databases, although it had been reported in 1 cutaneous melanoma sample (TCG-ER-1998) in the COSMIC and cBioPortal databases. Analysis of kinase activity in HEK293 cells showed that mutant activity was approximately 50% that of wildtype PRKCE, consistent with a partial loss-of-function mutation. Combining wildtype and mutant in the kinase assay did not demonstrate additivity, suggesting that a degree of dominant negativity is also a feature of E599K. Studies using patient lymphoblastoid cells demonstrated that the variant causes impaired AKT (164730) activation via compromised mTORC2 (601231) complex function. In the neonatal period, the patient was noted to have dysmorphic features, including prominent nose, high nasal bridge, and small chin, as well as an unusual distribution of fat and prune belly-like appearance of the abdomen. During follow-up she showed sparse scalp hair and hypodontia, as well as pale translucent skin with prominent vasculature and reduced body fat. Examination at age 13 years showed triangular face with broad forehead, prominent ears, deep-set palpebral fissures, prominent nasal root, and long nose with overhanging columella. She was developmentally age-appropriate and doing well in school. She had persistent primary dentition, lacking 8 adult teeth, and also showed pectus excavatum. Her body habitus was slender, and her face and extremities exhibited a paucity of fat with prominent vasculature. The authors stated that the proband's facial features were similar to those of classic SHORT syndrome, and noted that although she did not exhibit all of the cardinal manifestations described in the SHORT syndrome acronym, only half of patients with confirmed PIK3R1-associated SHORT syndrome showed 4 or more of the hallmark features.
Alcantara, D., Elmslie, F., Tetreault, M., Bareke, E., Hartley, T., Care4Rare Consortium, Majewski, J., Boycott, K., Innes, A. M., Dyment, D. A., O'Driscoll, M. SHORT syndrome due to a novel de novo mutation in PRKCE (protein kinase C-epsilon) impairing TORC2-dependent AKT activation. Hum. Molec. Genet. 26: 3713-3721, 2017. [PubMed: 28934384] [Full Text: https://doi.org/10.1093/hmg/ddx256]
Baines, C. P., Song, C.-X., Zheng, Y.-T., Wang, G.-W., Zhang, J., Wang, O.-L., Guo, Y., Bolli, R., Cardwell, E. M., Ping, P. Protein kinase C-epsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ. Res. 92: 873-880, 2003. [PubMed: 12663490] [Full Text: https://doi.org/10.1161/01.RES.0000069215.36389.8D]
Basta, P., Strickland, M. B., Holmes, W., Loomis, C. R., Ballas, L. M., Burns, D. J. Sequence and expression of human protein kinase C-epsilon. Biochim. Biophys. Acta 1132: 154-160, 1992. [PubMed: 1382605] [Full Text: https://doi.org/10.1016/0167-4781(92)90006-l]
Castrillo, A., Pennington, D. J., Otto, F., Parker, P. J., Owen, M. J., Bosca, L. Protein kinase C-epsilon is required for macrophage activation and defense against bacterial infection. J. Exp. Med. 194: 1231-1242, 2001. [PubMed: 11696589] [Full Text: https://doi.org/10.1084/jem.194.9.1231]
Chen, C.-H., Gray, M. O., Mochly-Rosen, D. Cardioprotection from ischemia by a brief exposure to physiological levels of ethanol: role of epsilon protein kinase C. Proc. Nat. Acad. Sci. 96: 12784-12789, 1999. [PubMed: 10536000] [Full Text: https://doi.org/10.1073/pnas.96.22.12784]
Chen, X.-N., Knauf, J. A., Gonsky, R., Wang, M., Lai, E. H., Chissoe, S., Fagin, J. A., Korenberg, J. R. From amplification to gene in thyroid cancer: a high-resolution mapped bacterial-artificial-chromosome resource for cancer chromosome aberrations guides gene discovery after comparative genome hybridization. Am. J. Hum. Genet. 63: 625-637, 1998. [PubMed: 9683604] [Full Text: https://doi.org/10.1086/301973]
Choi, D.-S., Wang, D., Yu, G.-Q., Zhu, G., Kharazia, V. N., Paredes, J. P., Chang, W. S., Deitchman, J. K., Mucke, L., Messing, R. O. PKC-epsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc. Nat. Acad. Sci. 103: 8215-8220, 2006. [PubMed: 16698938] [Full Text: https://doi.org/10.1073/pnas.0509725103]
Csukai, M., Chen, C.-H., De Matteis, M. A., Mochly-Rosen, D. The coatomer protein beta-prime-COP, a selective binding protein (RACK) for protein kinase C-epsilon. J. Biol. Chem. 272: 29200-29206, 1997. [PubMed: 9360998] [Full Text: https://doi.org/10.1074/jbc.272.46.29200]
Ding, L., Wang, H., Lang, W., Xiao, L. Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. J. Biol. Chem. 277: 35305-35313, 2002. [PubMed: 12121973] [Full Text: https://doi.org/10.1074/jbc.M201460200]
Hodge, C. W., Raber, J., McMahon, T., Walter, H., Sanchez-Perez, A. M., Olive, M. F., Mehmert, K., Morrow, A. L., Messing, R. O. Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase C-epsilon. J. Clin. Invest. 110: 1003-1010, 2002. [PubMed: 12370278] [Full Text: https://doi.org/10.1172/JCI15903]
Knauf, J. A., Elisei, R., Mochly-Rosen, D., Liron, T., Chen, X.-N., Gonsky, R., Korenberg, J. R., Fagin, J. A. Involvement of protein kinase C-epsilon (PKC-epsilon) in thyroid cell death: a truncated chimeric PKC-epsilon cloned from a thyroid cancer cell line protects thyroid cells from apoptosis. J. Biol. Chem. 274: 23414-23425, 1999. [PubMed: 10438519] [Full Text: https://doi.org/10.1074/jbc.274.33.23414]
Littler, C. M., Morris, K. G., Jr., Fagan, K. A., McMurtry, I. F., Messing, R. O., Dempsey, E. C. Protein kinase C-epsilon-null mice have decreased hypoxic pulmonary vasoconstriction. Am. J. Physiol. Heart Circ. Physiol. 284: H1321-H1331, 2003. [PubMed: 12505875] [Full Text: https://doi.org/10.1152/ajpheart.00795.2002]
Maeno-Hikichi, Y., Chang, S., Matsumura, K., Lai, M., Lin, H., Nakagawa, N., Kuroda, S., Zhang, J. A PKC-epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels. Nature Neurosci. 6: 468-475, 2003. [PubMed: 12665800] [Full Text: https://doi.org/10.1038/nn1041]
Premkumar, L. S., Ahern, G. P. Induction of vanilloid receptor channel activity by protein kinase C. Nature 408: 985-990, 2000. [PubMed: 11140687] [Full Text: https://doi.org/10.1038/35050121]