PRKCQ

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
PRKCQ
Protein PRKCQ PDB 1xjd.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPRKCQ, PRKCT, nPKC-theta, protein kinase C theta
External IDsMGI: 97601 HomoloGene: 21263 GeneCards: PRKCQ
Gene location (Human)
Chromosome 10 (human)
Chr.Chromosome 10 (human)[1]
Chromosome 10 (human)
Genomic location for PRKCQ
Genomic location for PRKCQ
Band10p15.1Start6,427,143 bp[1]
End6,580,301 bp[1]
RNA expression pattern
PBB GE PRKCQ 210038 at fs.png

PBB GE PRKCQ 210039 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_008859

RefSeq (protein)

NP_032885

Location (UCSC)Chr 10: 6.43 – 6.58 MbChr 2: 11.17 – 11.3 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[edit]

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[edit]

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 depleted from the region of immunological synapse, whereas in effector T cells, PKC θ is present.[6] As a result of costimulation 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 histons 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[edit]

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.[14]

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 specif to concrete isoforms of PKC.[6]s.

Interactions[edit]

PRKCQ has been shown to interact with:

PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway.[19]

Inhibitors[edit]

  • (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[20]

See also[edit]

References[edit]

  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:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ a b Baier G, Telford D, Giampa L, Coggeshall KM, Baier-Bitterlich G, Isakov N, Altman A (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". J Biol Chem. 268 (7): 4997–5004. PMID 8444877. 
  6. ^ a b c d e f Zanin-Zhorov, Alexandra; Dustin, Michael L.; Blazar, Bruce R. "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 3573858Freely accessible. 
  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, Xu-Dong; Gong, Yu; Chen, Zhi-Long; Gong, Bei-Ni; Xie, Ji-Ji; Zhong, Chuan-Qi; Wang, Qi-Long; Diao, Liang-Hui; Xu, Anlong (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. 
  10. ^ Zeng, Qibing; Luo, Peng; Gu, Junying; Liang, Bing; Liu, Qizhan; Zhang, Aihua. "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. 
  11. ^ a b Madouri, Fahima; Chenuet, Pauline; Beuraud, Chloé; Fauconnier, Louis; Marchiol, Tiffany; Rouxel, Nathalie; Ledru, Aurélie; Gallerand, Margaux; Lombardi, Vincent. "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. 
  12. ^ Li, Jasmine; Hardy, Kristine; Phetsouphanh, Chan; Tu, Wen Juan; Sutcliffe, Elissa L.; McCuaig, Robert; Sutton, Christopher R.; Zafar, Anjum; Munier, C. Mee Ling (2016-06-15). "Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation". J Cell Sci. 129 (12): 2448–2461. doi:10.1242/jcs.181248. ISSN 0021-9533. PMC 4920249Freely accessible. PMID 27149922. 
  13. ^ 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". Frontiers in Immunology. 3. doi:10.3389/fimmu.2012.00187. ISSN 1664-3224. 
  14. ^ Isakov, Noah. "PKCθ is a Key Regulator of T-cell Behavior and a Drug Target for T cell-mediated Diseases". Retrieved 14 February 2018. 
  15. ^ Bauer B, Krumböck N, Fresser F, Hochholdinger F, Spitaler M, Simm A, Uberall F, Schraven B, Baier G (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". J. Biol. Chem. 276 (34): 31627–34. doi:10.1074/jbc.M103098200. PMID 11410591. 
  16. ^ Ron D, Napolitano EW, Voronova A, Vasquez NJ, Roberts DN, Calio BL, Caothien RH, Pettiford SM, Wellik S, Mandac JB, Kauvar LM (July 1999). "Direct interaction in T-cells between thetaPKC and the tyrosine kinase p59fyn". J. Biol. Chem. 274 (27): 19003–10. doi:10.1074/jbc.274.27.19003. PMID 10383400. 
  17. ^ 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". J. Biol. Chem. 275 (3): 1902–9. doi:10.1074/jbc.275.3.1902. PMID 10636891. 
  18. ^ 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". J. Immunol. 164 (7): 3829–36. doi:10.4049/jimmunol.164.7.3829. PMID 10725744. 
  19. ^ Takeda K, Harada Y, Watanabe R, Inutake Y, Ogawa S, Onuki K, Kagaya S, Tanabe K, Kishimoto H, Abe R (December 2008). "CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis". Int. Immunol. 20 (12): 1507–15. doi:10.1093/intimm/dxn108. PMID 18829987. 
  20. ^ Jimenez JM, Boyall D, Brenchley G, Collier PN, Davis CJ, Fraysse D, Keily SB, Henderson J, Miller A, Pierard F, Settimo L, Twin HC, Bolton CM, Curnock AP, Chiu P, Tanner AJ, Young S (2013). "Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases". J. Med. Chem. 56 (5): 1799–810. doi:10.1021/jm301465a. PMID 23398373. 

Further reading[edit]