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{{Infobox_gene}}
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'''Protein kinase C theta''' ('''PKC-θ''') is an [[enzyme]] that in humans is encoded by the ''PRKCQ'' [[gene]].<ref name="pmid8444877">{{cite journal | vauthors = Baier G, Telford D, Giampa L, Coggeshall KM, Baier-Bitterlich G, Isakov N, Altman A | title = Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells | journal = J Biol Chem | volume = 268 | issue = 7 | pages = 4997–5004 | date = April 1993 | pmid = 8444877 | pmc = | doi = }}</ref> PKC-θ, a member of serine/threonine kinases, is mainly expressed in [[Hematopoietic cell|hematopoietic cells]]<ref name="pmid8444877" /> with high levels in [[Platelet|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.<ref name=":1" />
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_PRKCQ_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1xjd.
| PDB = {{PDB2|1xjd}}
| Name = Protein kinase C, theta
| HGNCid = 9410
| Symbol = PRKCQ
| AltSymbols =; MGC126514; MGC141919; PRKCT; nPKC-theta
| OMIM = 600448
| ECnumber = 
| Homologene = 21263
| MGIid = 97601
| GeneAtlas_image1 = PBB_GE_PRKCQ_210039_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PRKCQ_210038_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0000287 |text = magnesium ion binding}} {{GNF_GO|id=GO:0004674 |text = protein serine/threonine kinase activity}} {{GNF_GO|id=GO:0004697 |text = protein kinase C activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0019992 |text = diacylglycerol binding}}
| Component = {{GNF_GO|id=GO:0001772 |text = immunological synapse}} {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}}
| Process = {{GNF_GO|id=GO:0001558 |text = regulation of cell growth}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0007242 |text = intracellular signaling cascade}} {{GNF_GO|id=GO:0042102 |text = positive regulation of T cell proliferation}} {{GNF_GO|id=GO:0045086 |text = positive regulation of interleukin-2 biosynthetic process}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5588
    | Hs_Ensembl = ENSG00000065675
    | Hs_RefseqProtein = NP_006248
    | Hs_RefseqmRNA = NM_006257
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 10
    | Hs_GenLoc_start = 6509111
    | Hs_GenLoc_end = 6662269
    | Hs_Uniprot = Q04759
    | Mm_EntrezGene = 18761
    | Mm_Ensembl = ENSMUSG00000026778
    | Mm_RefseqmRNA = NM_008859
    | Mm_RefseqProtein = NP_032885
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 11090235
    | Mm_GenLoc_end = 11219079
    | Mm_Uniprot = Q3UK53
  }}
}}
'''Protein kinase C, theta''', also known as '''PRKCQ''', is a human [[gene]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
[[Protein kinase C]] (PKC) is a family of serine- and threonine-specific [[protein kinase]]s 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 ester]]s, 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 transcription factor|AP-1]], and may link the [[T cell receptor]] (TCR) signaling complex to the activation of the [[transcription factor]]s.<ref>{{cite web | title = Entrez Gene: PRKCQ protein kinase C, theta| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5588| accessdate = }}</ref> 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]].<ref name="pmid27094638">{{cite journal | vauthors = Michalczyk I, Toporkiewicz M, Dubielecka PM, Chorzalska A, Sikorski AF | title = PKC-θ is a negative regulator of TRAIL-induced and FADD-mediated apoptotic spectrin aggregation | journal = Folia Histochemica Et Cytobiologica | volume = 54 | issue = 1 | pages = 1–13 | year = 2016 | pmid = 27094638 | doi = 10.5603/FHC.a2016.0006 }}</ref>
{{PBB_Summary
| section_title =
| summary_text = Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and 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.<ref>{{cite web | title = Entrez Gene: PRKCQ protein kinase C, theta| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5588| accessdate = }}</ref>
}}


==See also==
=== The role of PKC-θ in T cells ===
PKC-θ has a role in the transduction of signals in [[T cell|T cells]], the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals from [[T-cell receptor|TCR]] and [[CD28]] receptors. A junction between an [[Antigen-presenting cell|APC]] (an [[Antigen-presenting cell|antigen presenting cell]]) and a [[T cell]] through their [[T-cell receptor|TCR]] and [[Major histocompatibility complex|MHC]] receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse of [[T cell|T cells]] between the cSMAC (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containing [[Lymphocyte function-associated antigen 1|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.<ref name=":1">{{Cite journal|last=Zanin-Zhorov|first=Alexandra|last2=Dustin|first2=Michael L.|last3=Blazar|first3=Bruce R.|title=PKC-θ function at the immunological synapse: prospects for therapeutic targeting|url=http://linkinghub.elsevier.com/retrieve/pii/S1471490611000743|journal=Trends in Immunology|volume=32|issue=8|pages=358–363|doi=10.1016/j.it.2011.04.007|pmc=3573858}}</ref> As a result of costimulation by CD28 and TCR, PKC-θ is sumoylated by [[Small ubiquitin-related modifier 1|SUMO1]] predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse.<ref>{{Cite journal|last=Wang|first=Xu-Dong|last2=Gong|first2=Yu|last3=Chen|first3=Zhi-Long|last4=Gong|first4=Bei-Ni|last5=Xie|first5=Ji-Ji|last6=Zhong|first6=Chuan-Qi|last7=Wang|first7=Qi-Long|last8=Diao|first8=Liang-Hui|last9=Xu|first9=Anlong|year = 2015|title=TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation|url=http://www.nature.com/doifinder/10.1038/ni.3259|journal=Nature Immunology|language=En|volume=16|issue=11|pages=1195–1203|pmid = 26390157|doi=10.1038/ni.3259|issn=1529-2916}}</ref> Subsequently, PKC-θ phosphorylates SPAK (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factor [[AP-1 transcription factor|AP-1]] (activating protein-1). PKC-θ also initiates the assembly of proteins [[CARD11|Carma-1]], [[BCL10|Bcl-10]] and [[MALT1|Malt-1]] by phosphorylation of [[CARD11|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).<ref>{{Cite journal|last=Zeng|first=Qibing|last2=Luo|first2=Peng|last3=Gu|first3=Junying|last4=Liang|first4=Bing|last5=Liu|first5=Qizhan|last6=Zhang|first6=Aihua|title=PKC θ-mediated Ca 2+ /NF-AT signalling pathway may be involved in T-cell immunosuppression in coal-burning arsenic-poisoned population|url=https://dx.doi.org/10.1016/j.etap.2017.08.005|journal=Environmental Toxicology and Pharmacology|volume=55|pages=44–50|doi=10.1016/j.etap.2017.08.005}}</ref> Thus, PKC-θ promotes inflammation in effector T cells.<ref name=":1" /> PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.<ref name=":2">{{Cite journal|last=Madouri|first=Fahima|last2=Chenuet|first2=Pauline|last3=Beuraud|first3=Chloé|last4=Fauconnier|first4=Louis|last5=Marchiol|first5=Tiffany|last6=Rouxel|first6=Nathalie|last7=Ledru|first7=Aurélie|last8=Gallerand|first8=Margaux|last9=Lombardi|first9=Vincent|title=Protein kinase Cθ controls type 2 innate lymphoid cell and T H 2 responses to house dust mite allergen|url=https://dx.doi.org/10.1016/j.jaci.2016.08.044|journal=Journal of Allergy and Clinical Immunology|volume=139|issue=5|pages=1650–1666|doi=10.1016/j.jaci.2016.08.044}}</ref> The kinase PKC-θ is crucial for function of [[Th2]] and [[T helper 17 cell|Th17]].<ref name=":1" /> 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.<ref>{{Cite journal|last=Li|first=Jasmine|last2=Hardy|first2=Kristine|last3=Phetsouphanh|first3=Chan|last4=Tu|first4=Wen Juan|last5=Sutcliffe|first5=Elissa L.|last6=McCuaig|first6=Robert|last7=Sutton|first7=Christopher R.|last8=Zafar|first8=Anjum|last9=Munier|first9=C. Mee Ling|date=2016-06-15|title=Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation|url=http://jcs.biologists.org/content/129/12/2448|journal=J Cell Sci|language=en|volume=129|issue=12|pages=2448–2461|doi=10.1242/jcs.181248|issn=0021-9533|pmid=27149922|pmc=4920249}}</ref> PKC-θ plays a role in anti-tumor activity of [[Natural killer cell|NK cells]]. It was observed that in mice without PKC-θ, [[MHC class I|MHCI]]-deficient tumors are more often.<ref>{{Cite journal|last=Anel|first=Alberto|last2=Aguiló|first2=Juan Ignacio|last3=Catalán|first3=Elena|last4=Garaude|first4=Johan|last5=Rathore|first5=Moeez Ghani|last6=Pardo|first6=Julián|last7=Villalba|first7=Martín|date=2012|title=Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity|url=http://journal.frontiersin.org/article/10.3389/fimmu.2012.00187/abstract|journal=Frontiers in Immunology|language=English|volume=3|doi=10.3389/fimmu.2012.00187|issn=1664-3224}}</ref>
 
=== 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)<ref name=":2" /> 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 [[Interleukin 2|IL-2]]. It was observed that animals without PKC-θ are resistant to some autoimmune diseases.<ref name=":1" /> PKC-θ could be a target of inhibitors in the therapy of [[Allergy|allergie]]<nowiki/>s.<ref name=":0">{{Cite web|url=https://www.omicsonline.org/pkc-is-a-key-regulator-of-t-cell-behavior-and-a-drug-target-for-t-cell-mediated-diseases-2155-9899.S12-008.php?aid=9512|title=PKC&theta; is a Key Regulator of T-cell Behavior and a Drug Target for T cell-mediated Diseases|last=Isakov|first=Noah|date=|website=|accessdate=14 February 2018}}</ref>
 
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 inhibitor]]<nowiki/>s have to be more specif to concrete isoforms of PKC.<ref name=":1" />s.
 
== Interactions ==
PRKCQ has been shown to [[Protein-protein interaction|interact]] with:
* [[AKT1]]<ref name = pmid11410591>{{cite journal | vauthors = Bauer B, Krumböck N, Fresser F, Hochholdinger F, Spitaler M, Simm A, Uberall F, Schraven B, Baier G | title = 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 = J. Biol. Chem. | volume = 276 | issue = 34 | pages = 31627–34 | date = August 2001 | pmid = 11410591 | doi = 10.1074/jbc.M103098200 }}</ref>
* [[FYN]],<ref name = pmid10383400>{{cite journal | vauthors = Ron D, Napolitano EW, Voronova A, Vasquez NJ, Roberts DN, Calio BL, Caothien RH, Pettiford SM, Wellik S, Mandac JB, Kauvar LM | title = Direct interaction in T-cells between thetaPKC and the tyrosine kinase p59fyn | journal = J. Biol. Chem. | volume = 274 | issue = 27 | pages = 19003–10 | date = July 1999 | pmid = 10383400 | doi = 10.1074/jbc.274.27.19003 }}</ref>
* [[GLRX3]],<ref name = pmid10636891>{{cite journal | vauthors = Witte S, Villalba M, Bi K, Liu Y, Isakov N, Altman A | title = 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 = J. Biol. Chem. | volume = 275 | issue = 3 | pages = 1902–9 | date = January 2000 | pmid = 10636891 | doi = 10.1074/jbc.275.3.1902 }}</ref>  and
* [[VAV1]].<ref name = pmid10725744>{{cite journal | vauthors = Hehner SP, Li-Weber M, Giaisi M, Dröge W, Krammer PH, Schmitz ML | title = Vav synergizes with protein kinase C theta to mediate IL-4 gene expression in response to CD28 costimulation in T cells | journal = J. Immunol. | volume = 164 | issue = 7 | pages = 3829–36 | date = April 2000 | pmid = 10725744 | doi = 10.4049/jimmunol.164.7.3829 }}</ref>
 
PRKCQ has been shown to phosphorylate [[CARD11]] as part of the [[NF-κB]] signaling pathway.<ref name=pmid18829987>{{cite journal | vauthors = Takeda K, Harada Y, Watanabe R, Inutake Y, Ogawa S, Onuki K, Kagaya S, Tanabe K, Kishimoto H, Abe R | title = CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis. | language =  | journal = Int. Immunol. | volume = 20 | issue = 12 | pages = 1507–15 | date = December 2008 | pmid = 18829987 | doi = 10.1093/intimm/dxn108 }}</ref>
 
== 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<ref name="pmid23398373">{{cite journal | vauthors = 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 | title = Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases | journal = J. Med. Chem. | volume = 56 | issue = 5 | pages = 1799–810 | year = 2013 | pmid = 23398373 | doi = 10.1021/jm301465a | url =  }}</ref>
 
== See also ==
*[[Protein kinase C]]
*[[Protein kinase C]]


==References==
== References ==
{{reflist|2}}
{{reflist}}
==Further reading==
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Meller N, Altman A, Isakov N | title = New perspectives on PKCtheta, a member of the novel subfamily of protein kinase C. | journal = Stem Cells | volume = 16 | issue = 3 | pages = 178–92 | year = 1998 | pmid = 9617893 | doi = 10.1002/stem.160178 }}
| citations =
* {{cite journal | vauthors = Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M | title = HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication. | journal = J. Biosci. | volume = 28 | issue = 3 | pages = 323–35 | year = 2004 | pmid = 12734410 | doi = 10.1007/BF02970151 }}
*{{cite journal | author=Meller N, Altman A, Isakov N |title=New perspectives on PKCtheta, a member of the novel subfamily of protein kinase C. |journal=Stem Cells |volume=16 |issue= 3 |pages= 178-92 |year= 1998 |pmid= 9617893 |doi= }}
* {{cite journal | vauthors = Ruegg CL, Strand M | title = A synthetic peptide with sequence identity to the transmembrane protein GP41 of HIV-1 inhibits distinct lymphocyte activation pathways dependent on protein kinase C and intracellular calcium influx. | journal = Cell. Immunol. | volume = 137 | issue = 1 | pages = 1–13 | year = 1991 | pmid = 1832084 | doi = 10.1016/0008-8749(91)90051-C }}
*{{cite journal | author=Greenway AL, Holloway G, McPhee DA, ''et al.'' |title=HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication. |journal=J. Biosci. |volume=28 |issue= 3 |pages= 323-35 |year= 2004 |pmid= 12734410 |doi= }}
* {{cite journal | vauthors = Chowdhury IH, Koyanagi Y, Kobayashi S, Hamamoto Y, Yoshiyama H, Yoshida T, Yamamoto N | title = The phorbol ester TPA strongly inhibits HIV-1-induced syncytia formation but enhances virus production: possible involvement of protein kinase C pathway. | journal = Virology | volume = 176 | issue = 1 | pages = 126–32 | year = 1990 | pmid = 1970444 | doi = 10.1016/0042-6822(90)90237-L }}
*{{cite journal | author=Ruegg CL, Strand M |title=A synthetic peptide with sequence identity to the transmembrane protein GP41 of HIV-1 inhibits distinct lymphocyte activation pathways dependent on protein kinase C and intracellular calcium influx. |journal=Cell. Immunol. |volume=137 |issue= 1 |pages= 1-13 |year= 1991 |pmid= 1832084 |doi= }}
* {{cite journal | vauthors = Ruegg CL, Strand M | title = Inhibition of protein kinase C and anti-CD3-induced Ca2+ influx in Jurkat T cells by a synthetic peptide with sequence identity to HIV-1 gp41. | journal = J. Immunol. | volume = 144 | issue = 10 | pages = 3928–35 | year = 1990 | pmid = 2139676 | doi =  }}
*{{cite journal | author=Chowdhury IH, Koyanagi Y, Kobayashi S, ''et al.'' |title=The phorbol ester TPA strongly inhibits HIV-1-induced syncytia formation but enhances virus production: possible involvement of protein kinase C pathway. |journal=Virology |volume=176 |issue= 1 |pages= 126-32 |year= 1990 |pmid= 1970444 |doi= }}
* {{cite journal | vauthors = Jakobovits A, Rosenthal A, Capon DJ | title = Trans-activation of HIV-1 LTR-directed gene expression by tat requires protein kinase C. | journal = EMBO J. | volume = 9 | issue = 4 | pages = 1165–70 | year = 1990 | pmid = 2182321 | pmc = 551792 | doi =  }}
*{{cite journal | author=Ruegg CL, Strand M |title=Inhibition of protein kinase C and anti-CD3-induced Ca2+ influx in Jurkat T cells by a synthetic peptide with sequence identity to HIV-1 gp41. |journal=J. Immunol. |volume=144 |issue= 10 |pages= 3928-35 |year= 1990 |pmid= 2139676 |doi=  }}
* {{cite journal | vauthors = Fields AP, Bednarik DP, Hess A, May WS | title = Human immunodeficiency virus induces phosphorylation of its cell surface receptor. | journal = Nature | volume = 333 | issue = 6170 | pages = 278–80 | year = 1988 | pmid = 3259291 | doi = 10.1038/333278a0 }}
*{{cite journal | author=Jakobovits A, Rosenthal A, Capon DJ |title=Trans-activation of HIV-1 LTR-directed gene expression by tat requires protein kinase C. |journal=EMBO J. |volume=9 |issue= 4 |pages= 1165-70 |year= 1990 |pmid= 2182321 |doi=  }}
* {{cite journal | vauthors = Chirmule N, Goonewardena H, Pahwa S, Pasieka R, Kalyanaraman VS, Pahwa S | title = HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells. | journal = J. Biol. Chem. | volume = 270 | issue = 33 | pages = 19364–9 | year = 1995 | pmid = 7642615 | doi = 10.1074/jbc.270.33.19364 }}
*{{cite journal | author=Fields AP, Bednarik DP, Hess A, May WS |title=Human immunodeficiency virus induces phosphorylation of its cell surface receptor. |journal=Nature |volume=333 |issue= 6170 |pages= 278-80 |year= 1988 |pmid= 3259291 |doi= 10.1038/333278a0 }}
* {{cite journal | vauthors = Chang JD, Xu Y, Raychowdhury MK, Ware JA | title = Molecular cloning and expression of a cDNA encoding a novel isoenzyme of protein kinase C (nPKC). A new member of the nPKC family expressed in skeletal muscle, megakaryoblastic cells, and platelets. | journal = J. Biol. Chem. | volume = 268 | issue = 19 | pages = 14208–14 | year = 1993 | pmid = 7686153 | doi =  }}
*{{cite journal | author=Chirmule N, Goonewardena H, Pahwa S, ''et al.'' |title=HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells. |journal=J. Biol. Chem. |volume=270 |issue= 33 |pages= 19364-9 |year= 1995 |pmid= 7642615 |doi= }}
* {{cite journal | vauthors = Erdel M, Baier-Bitterlich G, Duba C, Isakov N, Altman A, Utermann G, Baier G | title = Mapping of the human protein kinase C-theta (PRKCQ) gene locus to the short arm of chromosome 10 (10p15) by FISH. | journal = Genomics | volume = 25 | issue = 2 | pages = 595–7 | year = 1995 | pmid = 7790001 | doi = 10.1016/0888-7543(95)80068-W }}
*{{cite journal | author=Chang JD, Xu Y, Raychowdhury MK, Ware JA |title=Molecular cloning and expression of a cDNA encoding a novel isoenzyme of protein kinase C (nPKC). A new member of the nPKC family expressed in skeletal muscle, megakaryoblastic cells, and platelets. |journal=J. Biol. Chem. |volume=268 |issue= 19 |pages= 14208-14 |year= 1993 |pmid= 7686153 |doi=  }}
* {{cite journal | vauthors = Ward NE, Gravitt KR, O'Brian CA | title = Inhibition of protein kinase C by a synthetic peptide corresponding to cytoplasmic domain residues 828-848 of the human immunodeficiency virus type 1 envelope glycoprotein. | journal = Cancer Lett. | volume = 88 | issue = 1 | pages = 37–40 | year = 1995 | pmid = 7850771 | doi = 10.1016/0304-3835(94)03610-U }}
*{{cite journal | author=Erdel M, Baier-Bitterlich G, Duba C, ''et al.'' |title=Mapping of the human protein kinase C-theta (PRKCQ) gene locus to the short arm of chromosome 10 (10p15) by FISH. |journal=Genomics |volume=25 |issue= 2 |pages= 595-7 |year= 1995 |pmid= 7790001 |doi= }}
* {{cite journal | vauthors = Gupta S, Aggarwal S, Kim C, Gollapudi S | title = Human immunodeficiency virus-1 recombinant gp120 induces changes in protein kinase C isozymes--a preliminary report. | journal = Int. J. Immunopharmacol. | volume = 16 | issue = 3 | pages = 197–204 | year = 1994 | pmid = 8206685 | doi = 10.1016/0192-0561(94)90013-2 }}
*{{cite journal | author=Ward NE, Gravitt KR, O'Brian CA |title=Inhibition of protein kinase C by a synthetic peptide corresponding to cytoplasmic domain residues 828-848 of the human immunodeficiency virus type 1 envelope glycoprotein. |journal=Cancer Lett. |volume=88 |issue= 1 |pages= 37-40 |year= 1995 |pmid= 7850771 |doi= }}
* {{cite journal | vauthors = Parada NA, Cruikshank WW, Danis HL, Ryan TC, Center DM | title = IL-16- and other CD4 ligand-induced migration is dependent upon protein kinase C. | journal = Cell. Immunol. | volume = 168 | issue = 1 | pages = 100–6 | year = 1996 | pmid = 8599832 | doi = 10.1006/cimm.1996.0054 }}
*{{cite journal | author=Gupta S, Aggarwal S, Kim C, Gollapudi S |title=Human immunodeficiency virus-1 recombinant gp120 induces changes in protein kinase C isozymes--a preliminary report. |journal=Int. J. Immunopharmacol. |volume=16 |issue= 3 |pages= 197-204 |year= 1994 |pmid= 8206685 |doi= }}
* {{cite journal | vauthors = Conant K, Ma M, Nath A, Major EO | title = Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes. | journal = J. Virol. | volume = 70 | issue = 3 | pages = 1384–9 | year = 1996 | pmid = 8627654 | pmc = 189957 | doi = }}
*{{cite journal | author=Baier G, Telford D, Giampa L, ''et al.'' |title=Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells. |journal=J. Biol. Chem. |volume=268 |issue= 7 |pages= 4997-5004 |year= 1993 |pmid= 8444877 |doi= }}
* {{cite journal | vauthors = Smith BL, Krushelnycky BW, Mochly-Rosen D, Berg P | title = The HIV nef protein associates with protein kinase C theta. | journal = J. Biol. Chem. | volume = 271 | issue = 28 | pages = 16753–7 | year = 1996 | pmid = 8663223 | doi = 10.1074/jbc.271.17.9906 }}
*{{cite journal | author=Parada NA, Cruikshank WW, Danis HL, ''et al.'' |title=IL-16- and other CD4 ligand-induced migration is dependent upon protein kinase C. |journal=Cell. Immunol. |volume=168 |issue= 1 |pages= 100-6 |year= 1996 |pmid= 8599832 |doi= 10.1006/cimm.1996.0054 }}
* {{cite journal | vauthors = Meller N, Liu YC, Collins TL, Bonnefoy-Bérard N, Baier G, Isakov N, Altman A | title = Direct interaction between protein kinase C theta (PKC theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function. | journal = Mol. Cell. Biol. | volume = 16 | issue = 10 | pages = 5782–91 | year = 1996 | pmid = 8816492 | pmc = 231579 | doi =  }}
*{{cite journal | author=Conant K, Ma M, Nath A, Major EO |title=Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes. |journal=J. Virol. |volume=70 |issue= 3 |pages= 1384-9 |year= 1996 |pmid= 8627654 |doi= }}
* {{cite journal | vauthors = Holmes AM | title = In vitro phosphorylation of human immunodeficiency virus type 1 Tat protein by protein kinase C: evidence for the phosphorylation of amino acid residue serine-46. | journal = Arch. Biochem. Biophys. | volume = 335 | issue = 1 | pages = 8–12 | year = 1996 | pmid = 8914829 | doi = 10.1006/abbi.1996.0476 }}
*{{cite journal | author=Smith BL, Krushelnycky BW, Mochly-Rosen D, Berg P |title=The HIV nef protein associates with protein kinase C theta. |journal=J. Biol. Chem. |volume=271 |issue= 28 |pages= 16753-7 |year= 1996 |pmid= 8663223 |doi=  }}
* {{cite journal | vauthors = Monks CR, Kupfer H, Tamir I, Barlow A, Kupfer A | title = Selective modulation of protein kinase C-theta during T-cell activation. | journal = Nature | volume = 385 | issue = 6611 | pages = 83–6 | year = 1997 | pmid = 8985252 | doi = 10.1038/385083a0 }}
*{{cite journal | author=Meller N, Liu YC, Collins TL, ''et al.'' |title=Direct interaction between protein kinase C theta (PKC theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function. |journal=Mol. Cell. Biol. |volume=16 |issue= 10 |pages= 5782-91 |year= 1996 |pmid= 8816492 |doi= }}
* {{cite journal | vauthors = Datta R, Kojima H, Yoshida K, Kufe D | title = Caspase-3-mediated cleavage of protein kinase C theta in induction of apoptosis. | journal = J. Biol. Chem. | volume = 272 | issue = 33 | pages = 20317–20 | year = 1997 | pmid = 9252332 | doi = 10.1074/jbc.272.33.20317 }}
*{{cite journal | author=Holmes AM |title=In vitro phosphorylation of human immunodeficiency virus type 1 Tat protein by protein kinase C: evidence for the phosphorylation of amino acid residue serine-46. |journal=Arch. Biochem. Biophys. |volume=335 |issue= 1 |pages= 8-12 |year= 1996 |pmid= 8914829 |doi= 10.1006/abbi.1996.0476 }}
*{{cite journal | author=Monks CR, Kupfer H, Tamir I, ''et al.'' |title=Selective modulation of protein kinase C-theta during T-cell activation. |journal=Nature |volume=385 |issue= 6611 |pages= 83-6 |year= 1997 |pmid= 8985252 |doi= 10.1038/385083a0 }}
*{{cite journal  | author=Datta R, Kojima H, Yoshida K, Kufe D |title=Caspase-3-mediated cleavage of protein kinase C theta in induction of apoptosis. |journal=J. Biol. Chem. |volume=272 |issue= 33 |pages= 20317-20 |year= 1997 |pmid= 9252332 |doi=  }}
}}
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Latest revision as of 05:14, 23 May 2018

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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 depleted from the region of immunological synapse, whereas in effector T cells, PKC θ is present.[2] 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.[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 histons 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.[10]

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.[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.[15]

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[16]

See also

References

  1. ↑ 1.0 1.1 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.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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 3573858.
  3. ↑ "Entrez Gene: PRKCQ protein kinase C, theta".
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 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 4920249. 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". Frontiers in Immunology. 3. doi:10.3389/fimmu.2012.00187. ISSN 1664-3224.
  10. ↑ Isakov, Noah. "PKCθ is a Key Regulator of T-cell Behavior and a Drug Target for T cell-mediated Diseases". Retrieved 14 February 2018.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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

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