Biology:PRKCQ

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene.[1] PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells[1] with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.[2]

Function

Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipid-dependent protein kinase. This kinase is important for T-cell activation. It is required for the activation of the transcription factors NF-kappaB and AP-1, and may link the T cell receptor (TCR) signaling complex to the activation of the transcription factors.[3] PKC-θ also play a role in the apoptosis of lymphoid cells where it negatively influence and delay the aggregation of spectrin in an early phase of apoptosis.[4]

The role of PKC-θ in T cells

PKC-θ has a role in the transduction of signals in T cells, the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals from TCR and CD28 receptors. A junction between an APC (an antigen presenting cell) and a T cell through their TCR and MHC receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse of T cells between the cSMAC (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containing LFA-1 and ICAM-1). In regulatory T cells, PKC-θ is depleted from the region of immunological synapse, whereas in effector T cells, PKC-θ is present.[2] As a result of co-stimulation by CD28 and TCR, PKC-θ is sumoylated by SUMO1 predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse.[5] Subsequently, PKC-θ phosphorylates SPAK (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factor AP-1 (activating protein-1). PKC-θ also initiates the assembly of proteins Carma-1, Bcl-10 and Malt-1 by phosphorylation of Carma-1. This complex of three proteins activates the transcription factor NF-κB (nuclear factor-κB). Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT (nuclear factor of activated T cells).[6] Thus, PKC-θ promotes inflammation in effector T cells.[2] PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.[7] The kinase PKC-θ is crucial for function of Th2 and Th17.[2] Moreover, PKC-θ can translocate itself to the nucleus and by phosphorylation of histones increases the accessibility of transcriptional-memory-responsive genes in memory T cells.[8] PKC-θ plays a role in anti-tumor activity of NK cells. It was observed that in mice without PKC-θ, MHCI-deficient tumors are more often.[9]

The possible application of its inhibitors

Properties of PKC-θ make PKC-θ a good target for therapy in order to reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or by Th2 (causing allergies)[7] without diminishing the ability of T cells to get rid of viral-infected cells. Inhibitors could be used in T-cell mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and cause lower production of IL-2. It was observed that animals without PKC-θ are resistant to some autoimmune diseases.[2] PKC-θ could be a target of inhibitors in the therapy of allergies.

The problem is that inhibitors of PKC-θ targeting catalytic sites may have toxic effects because of low specificity (catalytic sites among PKCs are very similar). Allosteric inhibitors have to be more specific to concrete isoforms of PKC.[2] s.

Interactions

PRKCQ has been shown to interact with:

PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway.[14]

Inhibitors

  • (R)-2-((S)-4-(3-Chloro-5-fluoro-6-(1H-pyrazolo[3,4-b]pyridin- 3-yl)pyridin-2-yl)piperazin-2-yl)-3-methylbutan-2-ol[15]

See also

References

  1. ↑ 1.0 1.1 "Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells". J Biol Chem 268 (7): 4997–5004. April 1993. doi:10.1016/S0021-9258(18)53494-3. PMID 8444877. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Zanin-Zhorov, Alexandra; Dustin, Michael L.; Blazar, Bruce R. (2011). "PKC-θ function at the immunological synapse: prospects for therapeutic targeting". Trends in Immunology 32 (8): 358–363. doi:10.1016/j.it.2011.04.007. PMID 21733754. 
  3. ↑ "Entrez Gene: PRKCQ protein kinase C, theta". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5588. 
  4. ↑ "PKC-θ is a negative regulator of TRAIL-induced and FADD-mediated apoptotic spectrin aggregation". Folia Histochemica et Cytobiologica 54 (1): 1–13. 2016. doi:10.5603/FHC.a2016.0006. PMID 27094638. 
  5. ↑ Wang, Xu-Dong; Gong, Yu; Chen, Zhi-Long; Gong, Bei-Ni; Xie, Ji-Ji; Zhong, Chuan-Qi; Wang, Qi-Long; Diao, Liang-Hui et al. (2015). "TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation" (in En). Nature Immunology 16 (11): 1195–1203. doi:10.1038/ni.3259. ISSN 1529-2916. PMID 26390157. 
  6. ↑ Zeng, Qibing; Luo, Peng; Gu, Junying; Liang, Bing; Liu, Qizhan; Zhang, Aihua (2017). "PKC θ-mediated Ca 2+ /NF-AT signalling pathway may be involved in T-cell immunosuppression in coal-burning arsenic-poisoned population". Environmental Toxicology and Pharmacology 55: 44–50. doi:10.1016/j.etap.2017.08.005. PMID 28823652. 
  7. ↑ 7.0 7.1 Madouri, Fahima; Chenuet, Pauline; Beuraud, Chloé; Fauconnier, Louis; Marchiol, Tiffany; Rouxel, Nathalie; Ledru, Aurélie; Gallerand, Margaux et al. (2017). "Protein kinase Cθ controls type 2 innate lymphoid cell and T H 2 responses to house dust mite allergen". Journal of Allergy and Clinical Immunology 139 (5): 1650–1666. doi:10.1016/j.jaci.2016.08.044. PMID 27746240. 
  8. ↑ Li, Jasmine; Hardy, Kristine; Phetsouphanh, Chan; Tu, Wen Juan; Sutcliffe, Elissa L.; McCuaig, Robert; Sutton, Christopher R.; Zafar, Anjum et al. (2016-06-15). "Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation" (in en). J Cell Sci 129 (12): 2448–2461. doi:10.1242/jcs.181248. ISSN 0021-9533. PMID 27149922. 
  9. ↑ Anel, Alberto; Aguiló, Juan Ignacio; Catalán, Elena; Garaude, Johan; Rathore, Moeez Ghani; Pardo, Julián; Villalba, Martín (2012). "Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity" (in en). Frontiers in Immunology 3: 187. doi:10.3389/fimmu.2012.00187. ISSN 1664-3224. PMID 22783260. 
  10. ↑ "Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells". J. Biol. Chem. 276 (34): 31627–34. August 2001. doi:10.1074/jbc.M103098200. PMID 11410591. 
  11. ↑ "Direct interaction in T-cells between thetaPKC and the tyrosine kinase p59fyn". J. Biol. Chem. 274 (27): 19003–10. July 1999. doi:10.1074/jbc.274.27.19003. PMID 10383400. 
  12. ↑ "Inhibition of the c-Jun N-terminal kinase/AP-1 and NF-kappaB pathways by PICOT, a novel protein kinase C-interacting protein with a thioredoxin homology domain". J. Biol. Chem. 275 (3): 1902–9. January 2000. doi:10.1074/jbc.275.3.1902. PMID 10636891. 
  13. ↑ "Vav synergizes with protein kinase C theta to mediate IL-4 gene expression in response to CD28 costimulation in T cells". J. Immunol. 164 (7): 3829–36. April 2000. doi:10.4049/jimmunol.164.7.3829. PMID 10725744. 
  14. ↑ "CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis.". Int. Immunol. 20 (12): 1507–15. December 2008. doi:10.1093/intimm/dxn108. PMID 18829987. 
  15. ↑ "Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases". J. Med. Chem. 56 (5): 1799–810. 2013. doi:10.1021/jm301465a. PMID 23398373. 

Further reading



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