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PRKCQ

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PRKCQ
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPRKCQ, PRKCT, nPKC-theta, protein kinase C theta
External IDsOMIM: 600448; MGI: 97601; HomoloGene: 21263; GeneCards: PRKCQ; OMA:PRKCQ - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5588

18761

Ensembl

ENSG00000065675

ENSMUSG00000026778

UniProt

Q04759

Q02111

RefSeq (mRNA)

NM_008859
NM_178075

RefSeq (protein)

NP_032885

Location (UCSC)Chr 10: 6.43 – 6.58 MbChr 2: 11.18 – 11.31 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene.[5] PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells[5] 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.[6]

Function

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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.[7] 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.[8]

The role of PKC-θ in T cells

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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.[6] 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.[9] 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).[10] Thus, PKC-θ promotes inflammation in effector T cells.[6] PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.[11] The kinase PKC-θ is crucial for function of Th2 and Th17.[6] 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.[12] 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.[13]

The possible application of its inhibitors

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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)[11] 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.[6] 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.[6] s.

Interactions

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PRKCQ has been shown to interact with:

PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway.[18]

Inhibitors

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  • (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[19]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000065675 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026778 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Baier G, Telford D, Giampa L, Coggeshall KM, Baier-Bitterlich G, Isakov N, et al. (April 1993). "Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells". Journal of Biological Chemistry. 268 (7): 4997–5004. doi:10.1016/S0021-9258(18)53494-3. PMID 8444877.
  6. ^ a b c d e f Zanin-Zhorov A, Dustin ML, Blazar BR (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. PMC 3573858. PMID 21733754.
  7. ^ "Entrez Gene: PRKCQ protein kinase C, theta".
  8. ^ Michalczyk I, Toporkiewicz M, Dubielecka PM, Chorzalska A, Sikorski AF (2016). "PKC-θ is a negative regulator of TRAIL-induced and FADD-mediated apoptotic spectrin aggregation". Folia Histochemica et Cytobiologica. 54 (1): 1–13. doi:10.5603/FHC.a2016.0006. PMID 27094638.
  9. ^ Wang XD, Gong Y, Chen ZL, Gong BN, Xie JJ, Zhong CQ, et al. (2015). "TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation". Nature Immunology. 16 (11): 1195–1203. doi:10.1038/ni.3259. ISSN 1529-2916. PMID 26390157. S2CID 21498259.
  10. ^ Zeng Q, Luo P, Gu J, Liang B, Liu Q, Zhang A (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.
  11. ^ a b Madouri F, Chenuet P, Beuraud C, Fauconnier L, Marchiol T, Rouxel N, et al. (2017). "Protein kinase Cθ controls type 2 innate lymphoid cell and T H 2 responses to house dust mite allergen". The Journal of Allergy and Clinical Immunology. 139 (5): 1650–1666. doi:10.1016/j.jaci.2016.08.044. PMID 27746240.
  12. ^ Li J, Hardy K, Phetsouphanh C, Tu WJ, Sutcliffe EL, McCuaig R, et al. (2016-06-15). "Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation". Journal of Cell Science. 129 (12): 2448–2461. doi:10.1242/jcs.181248. ISSN 0021-9533. PMC 4920249. PMID 27149922.
  13. ^ Anel A, Aguilo JI, Catalan E, Garaude J, Rathore MG, Pardo J, et al. (2012). "Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity". Frontiers in Immunology. 3: 187. doi:10.3389/fimmu.2012.00187. ISSN 1664-3224. PMC 3389606. PMID 22783260.
  14. ^ Bauer B, Krumböck N, Fresser F, Hochholdinger F, Spitaler M, Simm A, et al. (August 2001). "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". Journal of Biological Chemistry. 276 (34): 31627–31634. doi:10.1074/jbc.M103098200. PMID 11410591.
  15. ^ Ron D, Napolitano EW, Voronova A, Vasquez NJ, Roberts DN, Calio BL, et al. (July 1999). "Direct interaction in T-cells between thetaPKC and the tyrosine kinase p59fyn". Journal of Biological Chemistry. 274 (27): 19003–19010. doi:10.1074/jbc.274.27.19003. PMID 10383400.
  16. ^ Witte S, Villalba M, Bi K, Liu Y, Isakov N, Altman A (January 2000). "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". Journal of Biological Chemistry. 275 (3): 1902–1909. doi:10.1074/jbc.275.3.1902. PMID 10636891.
  17. ^ Hehner SP, Li-Weber M, Giaisi M, Dröge W, Krammer PH, Schmitz ML (April 2000). "Vav synergizes with protein kinase C theta to mediate IL-4 gene expression in response to CD28 costimulation in T cells". Journal of Immunology. 164 (7). Baltimore, Md: 3829–3836. doi:10.4049/jimmunol.164.7.3829. PMID 10725744.
  18. ^ Takeda K, Harada Y, Watanabe R, Inutake Y, Ogawa S, Onuki K, et al. (December 2008). "CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis". International Immunology. 20 (12): 1507–1515. doi:10.1093/intimm/dxn108. PMID 18829987.
  19. ^ Jimenez JM, Boyall D, Brenchley G, Collier PN, Davis CJ, Fraysse D, et al. (2013). "Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases". Journal of Medicinal Chemistry. 56 (5): 1799–1810. doi:10.1021/jm301465a. PMID 23398373.

Further reading

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