PRKCQ

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.{{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 }} 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.{{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 | doi-access = free }}

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.{{Cite journal | vauthors = Zanin-Zhorov A, Dustin ML, Blazar BR | title = PKC-θ function at the immunological synapse: prospects for therapeutic targeting | journal = Trends in Immunology | volume = 32 | issue = 8 | pages = 358–363 | year = 2011 | pmid = 21733754 | pmc = 3573858 | doi = 10.1016/j.it.2011.04.007 }} 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.{{Cite journal | vauthors = Wang XD, Gong Y, Chen ZL, Gong BN, Xie JJ, Zhong CQ, Wang QL, Diao LH, Xu A, Han J, Altman A, Li Y | title = TCR-induced sumoylation of the kinase PKC-θ controls T cell synapse organization and T cell activation | journal = Nature Immunology | volume = 16 | issue = 11 | pages = 1195–1203 | year = 2015 | pmid = 26390157 | doi = 10.1038/ni.3259 | language = En | s2cid = 21498259 | issn = 1529-2916 }} 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).{{Cite journal | vauthors = Zeng Q, Luo P, Gu J, Liang B, Liu Q, Zhang A | title = PKC θ-mediated Ca 2+ /NF-AT signalling pathway may be involved in T-cell immunosuppression in coal-burning arsenic-poisoned population | journal = Environmental Toxicology and Pharmacology | volume = 55 | pages = 44–50 | year = 2017 | pmid = 28823652 | doi = 10.1016/j.etap.2017.08.005 }} Thus, PKC-θ promotes inflammation in effector T cells. PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.{{Cite journal | vauthors = Madouri F, Chenuet P, Beuraud C, Fauconnier L, Marchiol T, Rouxel N, Ledru A, Gallerand M, Lombardi V, Mascarell L, Marquant Q, Apetoh L, Erard F, Le Bert M, Trovero F, Quesniaux VF, Ryffel B, Togbe D | title = Protein kinase Cθ controls type 2 innate lymphoid cell and T H 2 responses to house dust mite allergen | journal = The Journal of Allergy and Clinical Immunology | volume = 139 | issue = 5 | pages = 1650–1666 | year = 2017 | pmid = 27746240 | doi = 10.1016/j.jaci.2016.08.044 | doi-access = free }} The kinase PKC-θ is crucial for function of Th2 and Th17. 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.{{Cite journal | vauthors = Li J, Hardy K, Phetsouphanh C, Tu WJ, Sutcliffe EL, McCuaig R, Sutton CR, Zafar A, Munier CM, Zaunders JJ, Xu Y, Theodoratos A, Tan A, Lim PS, Knaute T, Masch A, Zerweck J, Brezar V, Milburn PJ, Dunn J, Casarotto MG, Turner SJ, Seddiki N, Kelleher AD, Rao S | title = Nuclear PKC-θ facilitates rapid transcriptional responses in human memory CD4+ T cells through p65 and H2B phosphorylation | journal = Journal of Cell Science | volume = 129 | issue = 12 | pages = 2448–2461 | date = 2016-06-15 | pmid = 27149922 | pmc = 4920249 | doi = 10.1242/jcs.181248 | language = en | issn = 0021-9533 }} 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.{{Cite journal | vauthors = Anel A, Aguilo JI, Catalan E, Garaude J, Rathore MG, Pardo J, Villalba M | title = Protein Kinase C-θ (PKC-θ) in Natural Killer Cell Function and Anti-Tumor Immunity | journal = Frontiers in Immunology | volume = 3 | pages = 187 | date = 2012 | pmid = 22783260 | pmc = 3389606 | doi = 10.3389/fimmu.2012.00187 | language = en | issn = 1664-3224 | doi-access = free }}

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) 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. 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. s.

PRKCQ has been shown to interact with:

• AKT1{{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 = Journal of Biological Chemistry | volume = 276 | issue = 34 | pages = 31627–31634 | date = August 2001 | pmid = 11410591 | doi = 10.1074/jbc.M103098200 | doi-access = free }}
• FYN,{{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 = Journal of Biological Chemistry | volume = 274 | issue = 27 | pages = 19003–19010 | date = July 1999 | pmid = 10383400 | doi = 10.1074/jbc.274.27.19003 | doi-access = free }}
• GLRX3,{{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 = Journal of Biological Chemistry | volume = 275 | issue = 3 | pages = 1902–1909 | date = January 2000 | pmid = 10636891 | doi = 10.1074/jbc.275.3.1902 | doi-access = free }} and
• VAV1.{{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 = Journal of Immunology | location = Baltimore, Md | volume = 164 | issue = 7 | pages = 3829–3836 | date = April 2000 | pmid = 10725744 | doi = 10.4049/jimmunol.164.7.3829 | doi-access = free }}

PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway.{{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. | journal = International Immunology | volume = 20 | issue = 12 | pages = 1507–1515 | date = December 2008 | pmid = 18829987 | doi = 10.1093/intimm/dxn108 | doi-access = free }}

• (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{{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 = Journal of Medicinal Chemistry | volume = 56 | issue = 5 | pages = 1799–1810 | year = 2013 | pmid = 23398373 | doi = 10.1021/jm301465a }}

• Protein kinase C

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• {{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 | location = Dayton, Ohio | volume = 16 | issue = 3 | pages = 178–192 | year = 1998 | pmid = 9617893 | doi = 10.1002/stem.160178 | s2cid = 83896240 | doi-access = free }}
• {{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 = Journal of Biosciences | volume = 28 | issue = 3 | pages = 323–335 | year = 2004 | pmid = 12734410 | doi = 10.1007/BF02970151 | s2cid = 33749514 }}
• {{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 = Cellular Immunology | volume = 137 | issue = 1 | pages = 1–13 | year = 1991 | pmid = 1832084 | doi = 10.1016/0008-8749(91)90051-C | doi-access = free }}
• {{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 = 126–132 | year = 1990 | pmid = 1970444 | doi = 10.1016/0042-6822(90)90237-L }}
• {{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 = Journal of Immunology | location = Baltimore, Md | volume = 144 | issue = 10 | pages = 3928–3935 | year = 1990 | pmid = 2139676 | doi = 10.4049/jimmunol.144.10.3928 | doi-access = free }}
• {{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 = The EMBO Journal | volume = 9 | issue = 4 | pages = 1165–1170 | year = 1990 | pmid = 2182321 | pmc = 551792 | doi = 10.1002/j.1460-2075.1990.tb08223.x }}
• {{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 = 278–280 | year = 1988 | pmid = 3259291 | doi = 10.1038/333278a0 | bibcode = 1988Natur.333..278F | s2cid = 4254146 }}
• {{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 = Journal of Biological Chemistry | volume = 270 | issue = 33 | pages = 19364–19369 | year = 1995 | pmid = 7642615 | doi = 10.1074/jbc.270.33.19364 | doi-access = free }}
• {{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 = Journal of Biological Chemistry | volume = 268 | issue = 19 | pages = 14208–14214 | year = 1993 | pmid = 7686153 | doi = 10.1016/S0021-9258(19)85228-6 | doi-access = free }}
• {{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 = 595–597 | year = 1995 | pmid = 7790001 | doi = 10.1016/0888-7543(95)80068-W }}
• {{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 Letters | volume = 88 | issue = 1 | pages = 37–40 | year = 1995 | pmid = 7850771 | doi = 10.1016/0304-3835(94)03610-U }}
• {{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 = International Journal of Immunopharmacology | volume = 16 | issue = 3 | pages = 197–204 | year = 1994 | pmid = 8206685 | doi = 10.1016/0192-0561(94)90013-2 }}
• {{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 = Cellular Immunology | volume = 168 | issue = 1 | pages = 100–106 | year = 1996 | pmid = 8599832 | doi = 10.1006/cimm.1996.0054 | doi-access = free }}
• {{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 = Journal of Virology | volume = 70 | issue = 3 | pages = 1384–1389 | year = 1996 | pmid = 8627654 | pmc = 189957 | doi = 10.1128/JVI.70.3.1384-1389.1996 }}
• {{cite journal | vauthors = Smith BL, Krushelnycky BW, Mochly-Rosen D, Berg P | title = The HIV nef protein associates with protein kinase C theta. | journal = Journal of Biological Chemistry | volume = 271 | issue = 28 | pages = 16753–16757 | year = 1996 | pmid = 8663223 | doi = 10.1074/jbc.271.17.9906 | doi-access = free }}
• {{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 = Molecular and Cellular Biology | volume = 16 | issue = 10 | pages = 5782–5791 | year = 1996 | pmid = 8816492 | pmc = 231579 | doi = 10.1128/MCB.16.10.5782 }}
• {{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 = Archives of Biochemistry and Biophysics | volume = 335 | issue = 1 | pages = 8–12 | year = 1996 | pmid = 8914829 | doi = 10.1006/abbi.1996.0476 }}
• {{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 = 83–86 | year = 1997 | pmid = 8985252 | doi = 10.1038/385083a0 | bibcode = 1997Natur.385...83M | s2cid = 4255930 }}
• {{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 = Journal of Biological Chemistry | volume = 272 | issue = 33 | pages = 20317–20320 | year = 1997 | pmid = 9252332 | doi = 10.1074/jbc.272.33.20317 | doi-access = free }}

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{{Serine/threonine-specific protein kinases}}

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Category:EC 2.7.11