PRKCQ

PRKCQ
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XJD, 2ENJ, 2ENN, 2ENZ, 2JED, 4Q9Z, 4RA5, 5F9E
Identifiers
Aliases	PRKCQ, PRKCT, nPKC-theta, protein kinase C theta
External IDs	OMIM: 600448; MGI: 97601; HomoloGene: 21263; GeneCards: PRKCQ; OMA:PRKCQ - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10p15.1 Start 6,427,143 bp[1] End 6,580,301 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 A1|2 8.42 cM Start 11,176,919 bp[2] End 11,306,033 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in triceps brachii muscle glutes biceps brachii vastus lateralis muscle Skeletal muscle tissue of biceps brachii Skeletal muscle tissue of rectus abdominis thoracic diaphragm deltoid muscle muscle of thigh tibialis anterior muscle Top expressed in habenula ankle temporal muscle retinal pigment epithelium sternocleidomastoid muscle digastric muscle seminiferous tubule triceps brachii muscle thymus quadriceps femoris muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase C activity metal ion binding kinase activity protein binding ATP binding protein serine/threonine kinase activity protein kinase activity Cellular component cytoplasm cytosol membrane plasma membrane intracellular anatomical structure immunological synapse microtubule organizing center aggresome Biological process intracellular signal transduction regulation of transcription, DNA-templated positive regulation of telomere capping phosphorylation immune system process positive regulation of telomere maintenance via telomerase positive regulation of T-helper 2 cell activation positive regulation of interleukin-4 production axon guidance platelet activation Fc-epsilon receptor signaling pathway protein phosphorylation negative regulation of T cell apoptotic process negative regulation of insulin receptor signaling pathway positive regulation of T cell activation membrane protein ectodomain proteolysis positive regulation of NF-kappaB transcription factor activity peptidyl-serine phosphorylation positive regulation of T-helper 17 type immune response regulation of cell growth positive regulation of T cell proliferation positive regulation of telomerase activity cell chemotaxis positive regulation of interleukin-17 production inflammatory response T cell receptor signaling pathway regulation of platelet aggregation regulation of megakaryocyte differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5588 18761 Ensembl ENSG00000065675 ENSMUSG00000026778 UniProt Q04759 Q02111 RefSeq (mRNA) NM_001242413 NM_001282644 NM_001282645 NM_006257 NM_001323265 NM_001323266 NM_001323267 NM_008859 NM_178075 RefSeq (protein) NP_001229342 NP_001269573 NP_001269574 NP_001310194 NP_001310195 NP_001310196 NP_006248 NP_032885 Location (UCSC) Chr 10: 6.43 – 6.58 Mb Chr 2: 11.18 – 11.31 Mb PubMed search [3] [4]
Wikidata
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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

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

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

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

PRKCQ has been shown to interact with:

• AKT1^[14]
• FYN,^[15]
• GLRX3,^[16] and
• VAV1.^[17]

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

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^[19]

See also

• Protein kinase C

References

Further reading