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HGNC Approved Gene Symbol: PRKCB
Cytogenetic location: 16p12.2-p12.1 Genomic coordinates (GRCh38): 16:23,835,983-24,220,611 (from NCBI)
PRKCB is a member of the protein kinase C (PKC) gene family (see Coussens et al. (1986) and PRKCA, 176960).
Martin-Sierra et al. (2016) observed expression of PRKCB in human adult cochlea and semicircular canals. Analysis by quantitative PCR showed no significant difference between relative expression in the cochlea and vestibular tissues. PKCB II antibody labeling in rat cochlea demonstrated a tonotopic gradient in inner border and tectal cells. Quantification of the intensity of labeling revealed that apical-turn tectal cells, inner border cells, and afferent boutons innervating inner hair cells were the most intensely labeled; then middle- and basal-turn Dieters cells; and finally cochlear hair cells and vestibular hair cells, which were indistinguishable from background levels. Using gene expression data sets obtained from apical, middle, and basal turns of the mouse cochlea (Yoshimura et al., 2014) to predict signaling pathways associated with tonotopia yielded the axonal guidance signaling pathway, involving 28 genes, as the top candidate.
Greenham et al. (1998) determined the genomic structure of the PRKCB1 gene. The PRKCB1 gene consists of 18 exons spanning 375 kb, with a particularly large intron of over 150 kb between exons 2 and 3. Exons range from 32 to 174 bp in length.
Francke et al. (1989) stated that the most likely location of PRKCB1 is chromosome 16p11.2.
The 66-kD isoform of the growth factor adaptor SHC, p66(SHC) (600560), translates oxidative damage into cell death by acting as a reactive oxygen species producer within mitochondria. Pinton et al. (2007) demonstrated that protein kinase C-beta, activated by oxidative conditions in the cell, induces phosphorylation of p66(SHC) and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase PIN1 (601052). Once imported, p66(SHC) causes alterations of mitochondrial calcium ion responses and 3-dimensional structure, thus causing apoptosis. Pinton et al. (2007) concluded that their data identified a signaling route that activates an apoptotic inducer shortening the life span.
Metzger et al. (2010) demonstrated that phosphorylation of histone H3 (see 602810) at threonine-6 (H3T6) by PKC-beta-1 is the key event that prevents lysine-specific demethylase-1 (LSD1; 609132) from demethylating H3K4 during androgen-receptor (AR; 313700)-dependent gene activation. In vitro, histone H3 peptides methylated at lysine-4 and phosphorylated at threonine-6 were no longer LSD1 substrates. In vivo, PKC-beta-1 colocalized with AR and LSD1 on target gene promoters and phosphorylated H3T6 after androgen-induced gene expression. RNAi-mediated knockdown of PKC-beta-1 abrogated H3T6 phosphorylation, enhanced demethylation at H3K4, and inhibited AR-dependent transcription. Activation of PKCB1 requires androgen-dependent recruitment of the gatekeeper kinase protein kinase C-related kinase-1 (PRK1; 601032). Notably, increased levels of PKCB1 and phosphorylated H3T6 (H3T6ph) positively correlated with high Gleason scores of prostate carcinomas, and inhibition of PKC-beta-1 blocked AR-induced tumor cell proliferation in vitro and cancer progression of tumor xenografts in vivo. Together, Metzger et al. (2010) concluded that androgen-dependent kinase signaling leads to the writing of the new chromatin mark H3T6ph, which in consequence prevents removal of active methyl marks from H3K4 during AR-stimulated gene expression.
Associations Pending Confirmation
For discussion of a possible association between variation in the PRKCB1 gene and Meniere disease, see 156000.
Leitges et al. (1996) found that mice homozygous for a targeted disruption of the Prkcb1 gene develop an immunodeficiency characterized by impaired humoral immune responses and reduced cellular responses of B cells similar to X-linked immunodeficiency (Xid) in mice (see 300300). Thus, they concluded that the 2 isoforms, PKC-beta-I (PRKCB1) and PKC-beta-II (PRKCB2), play an important role in B-cell activation and may be functionally linked to Bruton tyrosine kinase (300300) in antigen receptor-mediated signal transduction.
Bowman et al. (1997) found that cardiomyocyte-specific expression of a constitutively active bovine Pkcb mutant in adult mice significantly increased heart weight and heart/body weight ratio. Histologic evaluation showed mild hypertrophy associated with impaired diastolic relaxation. Expression of the Pkcb mutant in newborn mice caused sudden death due to cardiac arrhythmia associated with abnormalities in regulation of intracellular calcium.
Su et al. (2002) showed that mice lacking Prkcb are unable to activate Nfkb (164011) and promote cell survival in B cells upon BCR signaling, or even in mast cells which, unlike B cells, also express Prkcq (600448). The failure to activate Nfkb is associated with a lack of Ikba (164008) degradation as well as an absence of Ikka (600664) phosphorylation activity. Prkcb -/- mice, lacking the Prkcb enzyme in lipid rafts after BCR stimulation, are also unable to recruit Ikka and Ikkb (603258) to the rafts in B cells and have a reduced capacity to recruit other members of the BCR signalosome. However, Prkcb-deficient mice, unlike Xid mice, do have mature B cells expressing IgM and IgD, suggesting that the cells are maintained by an alternative Nfkb-activating pathway, e.g., through CD40 (109535). Su et al. (2002) observed that specific Prkcb small molecule inhibitors block the survival of non-Hodgkin diffuse large B cell lymphoma (DLBCL) cell lines, with the effective dose depending on the level of cellular Prkcb. DLBCL lines not expressing Prkcb were not susceptible to the inhibitors. Su et al. (2002) proposed that PRKCB inhibitors and inhibitors of other PRKC isoforms may be effective in treating disorders characterized by dysregulated NFKB survival signaling.
The curly tail mutant mouse provides a model of folate-resistant neural tube defects (NTD; see 608317), in which defects can be prevented by inositol therapy in early pregnancy. Cogram et al. (2004) investigated the molecular mechanism by which inositol prevents mouse NTDs. They examined neurulation-stage embryos for PKC expression and applied PKC inhibitors to curly tail embryos developing in culture. Application of peptide inhibitors to neurulation-stage embryos revealed an absolute dependence on the activity of PRKCB1 and PRKCG (176980) for prevention of NTDs by inositol, and partial dependence on PRKCZ (176982), whereas PRKCA, PRKCB2, PRKCD (176977), and PRKCE (176975) were dispensable. Defective proliferation of hindgut cells was a key component of the pathogenic sequence leading to NTDs in curly tail mice. Hindgut cell proliferation was stimulated specifically by inositol, an effect that required activation of PRKCB1. Cogram et al. (2004) proposed an essential role for PRKCB1 and PRKCG in mediating the prevention of mouse NTDs by inositol.
Using chemical mutagenesis, followed by immunization and screening, Teh et al. (2013) isolated strains of inbred mice with semidominant mutations in Prkcb1 causing selective deficits in T cell-independent antibody responses against polysaccharide, but not protein, antigens. The ser552-to-pro (S552P) mutation, in helix G within the kinase domain, resulted in almost complete loss of active autophosphorylated Prkcb1 without affecting Prkcb2. There were diminished serum IgM and IgG3 and T cell-independent antibody responses in mice with the S552P mutation. Teh et al. (2013) concluded that missense mutations in PRKCB may contribute to population variability in anti-polysaccharide antibody levels.
Bowman, J. C., Steinberg, S. F., Jiang, T., Geenen, D. L., Fishman, G. I., Buttrick, P. M. Expression of protein kinase C-beta in the heart causes hypertrophy in adult mice and sudden death in neonates. J. Clin. Invest. 100: 2189-2195, 1997. [PubMed: 9410895] [Full Text: https://doi.org/10.1172/JCI119755]
Cogram, P., Hynes, A., Dunlevy, L. P. E., Greene, N. D. E., Copp, A. J. Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol. Hum. Molec. Genet. 13: 7-14, 2004. [PubMed: 14613966] [Full Text: https://doi.org/10.1093/hmg/ddh003]
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]
Francke, U., Darras, B. T., Zander, N. F., Kilimann, M. W. Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13. Am. J. Hum. Genet. 45: 276-282, 1989. [PubMed: 2757032]
Greenham, J., Adams, M., Doggett, N., Mole, S. Elucidation of the exon-intron structure and size of the human protein kinase C beta gene (PRKCB). Hum. Genet. 103: 483-487, 1998. [PubMed: 9856494] [Full Text: https://doi.org/10.1007/s004390050854]
Leitges, M., Schmedt, C., Guinamard, R., Davoust, J., Schaal, S., Stabel, S., Tarakhovsky, A. Immunodeficiency in protein kinase C-beta-deficient mice. Science 273: 788-791, 1996. [PubMed: 8670417] [Full Text: https://doi.org/10.1126/science.273.5276.788]
Martin-Sierra, C., Requena, T., Frejo, L., Price, S. D., Gallego-Martinez, A., Batuecas-Caletrio, A., Santos-Perez, S., Soto-Varela, A., Lysakowski, A., Lopez-Escamez, J. A. A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease. Hum. Molec. Genet. 25: 3407-3415, 2016. [PubMed: 27329761] [Full Text: https://doi.org/10.1093/hmg/ddw183]
Metzger, E., Imhof, A., Patel, D., Kahl, P., Hoffmeyer, K., Friedrichs, N., Muller, J. M., Greschik, H., Kirfel, J., Ji, S., Kunowska, N., Beisenherz-Huss, C., Gunther, T., Buettner, R., Schule, R. Phosphorylation of histone H3T6 by PKC-beta-1 controls demethylation at histone H3K4. Nature 464: 792-796, 2010. [PubMed: 20228790] [Full Text: https://doi.org/10.1038/nature08839]
Pinton, P., Rimessi, A., Marchi, S., Orsini, F., Migliaccio, E., Giorgio, M., Contursi, C., Minucci, S., Mantovani, F., Wieckowski, M. R., Del Sal, G., Pelicci, P. G., Rizzuto, R. Protein kinase C-beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66(Shc) Science 315: 659-663, 2007. [PubMed: 17272725] [Full Text: https://doi.org/10.1126/science.1135380]
Su, T. T., Guo, B., Kawakami, Y., Sommer, K., Chae, K., Humphries, L. A., Kato, R. M., Kang, S., Patrone, L., Wall, R., Teitell, M., Leitges, M., Kawakami, T., Rawlings, D. J. PKC-beta controls I-kappa-B kinase lipid raft recruitment and activation in response to BCR signaling. Nature Immun. 3: 780-786, 2002. [PubMed: 12118249] [Full Text: https://doi.org/10.1038/ni823]
Teh, C. E., Horikawa, K., Arnold, C. N., Beutler, B., Kucharska, E. M., Vinuesa, C. G., Bertram, E. M., Goodnow, C. C., Enders, A. Heterozygous mis-sense mutations in Prkcb as a critical determinant of anti-polysaccharide antibody formation. Genes Immunity 14: 223-233, 2013. [PubMed: 23552399] [Full Text: https://doi.org/10.1038/gene.2013.11]
Yoshimura, H., Takumi, Y., Nishio, S., Suzuki, N., Iwasa, Y., Usami, S. Deafness gene expression patterns in the mouse cochlea found by microarray analysis. PLoS One 9: e92547, 2014. Note: Electronic Article. [PubMed: 24676347] [Full Text: https://doi.org/10.1371/journal.pone.0092547]