HGNC Approved Gene Symbol: PRKCQ
Cytogenetic location: 10p15.1 Genomic coordinates (GRCh38): 10:6,394,097-6,580,646 (from NCBI)
Members of the protein kinase C (PKC) family of serine/threonine kinases play critical roles in the regulation of cellular differentiation and proliferation of diverse cell types. In an attempt to find PKC isoforms involved in growth control and/or activation of T lymphocytes, Baier et al. (1993) used a human peripheral blood lymphocyte-derived cDNA library to identify a novel PKC isoform, termed PKC-theta. The gene encodes a protein of approximately 80 kD, expressed predominantly in lymphoid tissues and hematopoietic cell lines, particularly T cells.
By fluorescence in situ hybridization, Erdel et al. (1995) assigned the PRKCQ gene to chromosome 10p15. Blanco and Brown (1997) mapped the mouse Prkcq homolog to chromosome 2 by analysis of an interspecific backcross.
In mouse mammary tumors, Belguise and Sonenshein (2007) identified Prkcq as a positive regulator of c-Rel (REL; 164910) transcriptional activity, as well as downstream target genes. In human breast cancer cell lines, there was an inverse correlation between ESR1 (133430) and PRKCQ mRNA, and PRKCQ was found to inhibit ESR1 expression via activation of AKT1 (164730). Belguise and Sonenshein (2007) concluded that PRKCQ plays a pivotal role in mammary tumorigenesis by activating AKT1, which ultimately leads to derepression of c-Rel through inhibition of ESR1.
Zanin-Zhorov et al. (2010) showed that PKC-theta recruitment to the immunologic synapse is required for full effector T cell (T-eff) activation. In contrast, PKC-theta was sequestered away from the regulatory T cell (T-reg) immunologic synapse. Furthermore, PKC-theta blockade enhanced T-reg function, demonstrating that PKC-theta inhibits T-reg-mediated suppression. Inhibition of PKC-theta protected T-reg cells from inactivation by TNF-alpha (191160), restored activity of defective T-regs from rheumatoid arthritis (RA; 180300) patients, and enhanced protection of mice from inflammatory colitis. Zanin-Zhorov et al. (2010) concluded that T-reg cells freed of PKC-theta-mediated inhibition can function in the presence of inflammatory cytokines.
Sun et al. (2000) demonstrated that PKC-theta is essential for T-cell antigen receptor (TCR)-mediated T-cell activation, but dispensable during TCR-dependent thymocyte development. They generated mice deficient in Pkc-theta by homologous recombination. Mutant mice were normal and fertile. TCR-initiated NF-kappa-B (see 164011) activation was absent from Pkc-theta -/- mature T lymphocytes, but was intact in thymocytes. Activation of NF-kappa-B by tumor necrosis factor-alpha (191160) and interleukin-1 (see 147760) was unaffected in the mutant mice. Induction of Jnk (see 601158) was normal in T cells from mutant mice. Sun et al. (2000) concluded that PKC-theta functions in a unique pathway that links the TCR signaling complex to the activation of NF-kappa-B in mature T lymphocytes.
Using hyperinsulinemic-euglycemic clamps, Kim et al. (2004) demonstrated that skeletal muscle and hepatic insulin action did not differ between wildtype and Pkc-theta-null mice. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the wildtype mice that was associated with 40 to 50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS1; 147545) and IRS1-associated PI3K (see 171834) activity. In contrast, Pkc-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. Kim et al. (2004) concluded that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle.
Tan et al. (2006) found that Pkc-theta -/- mice resisted development of experimental allergic encephalomyelitis (EAE), a model of central nervous system (CNS) autoimmune disease. Flow cytometric and histopathologic analyses revealed a profound reduction in T-cell and macrophage infiltration and demyelination. Stimulation of splenic T cells from Pkc-theta -/- mice resulted in significantly reduced production of Ifng (147570) and Il17 (603149), despite comparable levels of Il2 (147680) and Il4 (147780) and no difference in lymphoproliferation. After TCR activation, Pkc-theta -/- T cells failed to upregulate the adhesion molecule Lfa1 (see ITGB2; 600065). Immunohistochemical analysis showed reduced expression of Il17 in the CNS of Pkc-theta -/- mice. Tan et al. (2006) concluded that PKC-theta is important in the regulation of multiple T-cell functions necessary for development of autoimmune disease.
Baier, G., Telford, D., Giampa, L., Coggeshall, K. M., Baier-Bitterlich, G., Isakov, N., Altman, A. Molecular cloning and characterization of PKC-theta, a novel member of the protein (PKC) gene family expressed predominantly in hematopoietic cells. J. Biol. Chem. 268: 4997-5004, 1993. [PubMed: 8444877]
Belguise, K., Sonenshein, G. E. PKC-theta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor-alpha synthesis. J. Clin. Invest. 117: 4009-4021, 2007. [PubMed: 18037997] [Full Text: https://doi.org/10.1172/JCI32424]
Blanco, G., Brown, S. D. M. Genetic mapping of protein kinase C theta (Pkcq) to mouse chromosome 2. Mammalian Genome 8: 70-71, 1997. [PubMed: 9021158] [Full Text: https://doi.org/10.1007/s003359900355]
Erdel, M., Baier-Bitterlich, G., Duba, C., Isakov, N., Altman, A., Utermann, G., Baier, G. Mapping of the human protein kinase C-theta (PRKCQ) gene locus to the short arm of chromosome 10 (10p15) by FISH. Genomics 25: 595-597, 1995. [PubMed: 7790001] [Full Text: https://doi.org/10.1016/0888-7543(95)80068-w]
Kim, J. K., Fillmore, J. J., Sunshine, M. J., Albrecht, B., Higashimori, T., Kim, D.-W., Liu, Z.-X., Soos, T. J., Cline, G. W., O'Brien, W. R., Littman, D. R., Shulman, G. I. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114: 823-827, 2004. [PubMed: 15372106] [Full Text: https://doi.org/10.1172/JCI22230]
Sun, Z., Arendt, C. W., Ellmeier, W., Schaeffer, E. M., Sunshine, M. J., Gandhi, L., Annes, J., Petrzilka, D., Kupfer, A., Schwartzberg, P. L., Littman, D. R. PKC-theta is required for TCR-induced NF-kappa-B activation in mature but not immature T lymphocytes. Nature 404: 402-407, 2000. [PubMed: 10746729] [Full Text: https://doi.org/10.1038/35006090]
Tan, S.-L., Zhao, J., Bi, C., Chen, X. C., Hepburn, D. L., Wang, J., Sedgwick, J. D., Chintalacharuvu, S. R., Na, S. Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase C-theta-deficient mice. J. Immun. 176: 2872-2879, 2006. [PubMed: 16493044] [Full Text: https://doi.org/10.4049/jimmunol.176.5.2872]
Zanin-Zhorov, A., Ding, Y., Kumari, S., Attur, M., Hippen, K. L., Brown, M., Blazar, B. R., Abramson, S. B., Lafaille, J. J., Dustin, M. L. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328: 372-376, 2010. Note: Erratum: Science 328: 974 only, 2010. [PubMed: 20339032] [Full Text: https://doi.org/10.1126/science.1186068]