The yin and yang of protein kinase c-theta (PKCθ). A novel drug target for selective immunosuppression

Advances in Pharmacology

Volumn 66, Issue , 2013, Pages 267-312

  Zhang, Elizabeth Yan ^a   Kong, Kok Fai ^a   Altman, Amnon ^a  

^a LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY   (United States)

Author keywords

Autoimmunity; PKC ; Signaling; T cell activation; TCR; Treg

Indexed keywords

CD28 ANTIGEN; CD69 ANTIGEN; I KAPPA B KINASE ALPHA; I KAPPA B KINASE BETA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR ALPHA; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN BAD; PROTEIN KINASE C ALPHA; PROTEIN KINASE C BETA; PROTEIN KINASE C DELTA; PROTEIN KINASE C THETA; STRESS ACTIVATED PROTEIN KINASE; T LYMPHOCYTE RECEPTOR; TACROLIMUS; TRANSCRIPTION FACTOR NFAT;

ALLELE; ALLERGIC ENCEPHALOMYELITIS; ANTIBODY RESPONSE; APOPTOSIS; ARTICLE; BINDING SITE; CALCIUM SIGNALING; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DEATH; CELL MATURATION; CELL SURVIVAL; CELLULAR IMMUNITY; CHROMATIN IMMUNOPRECIPITATION; CHROMOSOME MAP; CYTOKINE PRODUCTION; DRUG TARGETING; ENZYME ACTIVATION; EXON; G1 PHASE CELL CYCLE CHECKPOINT; GASTROINTESTINAL STROMAL TUMOR; GENE DELETION; GENETIC ASSOCIATION; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNOSTIMULATION; IMMUNOSUPPRESSIVE TREATMENT; INNATE IMMUNITY; LYMPHOCYTE ACTIVATION; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE PROLIFERATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; PSORIASIS; RHEUMATOID ARTHRITIS; SINGLE NUCLEOTIDE POLYMORPHISM; TH17 CELL; THERAPY EFFECT; UPREGULATION;

EID: 84874509963     PISSN: 10543589     EISSN: 15578925     Source Type: Book Series    
DOI: 10.1016/B978-0-12-404717-4.00006-8     Document Type: Chapter

References (214)

1. Abb J., Bayliss G.J., Deinhardt F. Lymphocyte activation by the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA). Journal of Immunology 1979, 122:1639-1642.
2. Aguilo J.I., Garaude J., Pardo J., Villalba M., Anel A. Protein kinase C-θ is required for NK cell activation and in vivo control of tumor progression. Journal of Immunology 2009, 182:1972-1981.
3. 2+ signaling by PKCθ in restimulated T cells via a Tec kinase-dependent pathway. European Journal of Immunology 2004, 34:2001-2011.
4. Anderson K., Fitzgerald M., Dupont M., Wang T., Paz N., Dorsch M., et al. Mice deficient in PKC θ demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases. Autoimmunity 2006, 39:469-478.
5. Anel A., Aguilo J.I., Catalan E., Garaude J., Rathore M.G., Pardo J., et al. Protein kinase C-θ (PKC-θ) in natural killer cell function and anti-tumor immunity. Frontiers in Immunology 2012, 3:187.
6. Baeke F., Takiishi T., Korf H., Gysemans C., Mathieu C. Vitamin D: modulator of the immune system. Current Opinion in Pharmacology 2010, 10:482-496.
7. Baier G., Wagner J. PKC inhibitors: potential in T cell-dependent immune diseases. Current Opinion in Cell Biology 2009, 21:262-267.
8. Baier G., Telford D., Giampa L., Coggeshall K.M., Baier-Bitterlich G., Isakov N., et al. Molecular cloning and characterization of PKC θ, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells. Journal of Biological Chemistry 1993, 268:4997-5004.
9. Baier G. The PKC gene module: molecular biosystematics to resolve its T cell functions. Immunological Reviews 2003, 192:64-79.
10. Baier-Bitterlich G., Uberall F., Bauer B., Fresser F., Wachter H., Grunicke H., et al. Protein kinase C-θ isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes. Molecular and Cellular Biology 1996, 16:1842-1850.
11. Balogh G., de Boland A.R., Boland R., Barja P. Effect of 1,25OH(2)-vitamin D3 on the activation of natural killer cells: role of protein kinase C and extracellular calcium. Experimental and Molecular Pathology 1999, 67:63-74.
12. Barouch-Bentov R., Lemmens E.E., Hu J., Janssen E.M., Droin N.M., Song J., et al. Protein kinase C-θ is an early survival factor required for differentiation of effector CD8+ T cells. Journal of Immunology 2005, 175:5126-5134.
13. Bauer B., Krumbock N., Ghaffari-Tabrizi N., Kampfer S., Villunger A., Wilda M., et al. T cell expressed PKCθ demonstrates cell-type selective function. European Journal of Immunology 2000, 30:3645-3654.
14. Beal A.M., Anikeeva N., Varma R., Cameron T.O., Norris P.J., Dustin M.L., et al. Protein kinase C θ regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL. Journal of Immunology 2008, 181:4815-4824.
15. Belguise K., Sonenshein G.E. PKCθ promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor α synthesis. Journal of Clinical Investigation 2007, 117:4009-4021.
16. Bennett C.L., Christie J., Ramsdell F., Brunkow M.E., Ferguson P.J., Whitesell L., et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics 2001, 27:20-21.
17. Berg-Brown N.N., Gronski M.A., Jones R.G., Elford A.R., Deenick E.K., Odermatt B., et al. PKCθ signals activation versus tolerance in vivo. Journal of Experimental Medicine 2004, 1999:743-752.
18. Bertolotto C., Maulon L., Filippa N., Baier G., Auberger P. Protein kinase C θ and ε promote T-cell survival by a rsk-dependent phosphorylation and inactivation of BAD. Journal of Biological Chemistry 2000, 275:37246-37250.
19. Bi K., Tanaka Y., Coudronniere N., Hong S., Sugie K., van Stipdonk M.J.B., et al. Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation. Nature Immunology 2001, 2:556-563.
20. Bigaud M., Wieczorek G., Beerli C., Audet M., Blancher A., Heusser C., et al. Sotrastaurin (AEB071) alone and in combination with cyclosporine A prolongs survival times of non-human primate recipients of life-supporting kidney allografts. Transplantation 2012, 93:156-164.
21. Blay P., Astudillo A., Buesa J.M., Campo E., Abad M., Garcia-Garcia J., et al. Protein kinase C θ is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clinical Cancer Research 2004, 10:4089-4095.
22. Bretscher P.A., Cohn M. Minimal model for the mechanism of antibody induction and paralysis by antigen. Nature 1968, 220:444-448.
23. Bromley S.K., Burack W.R., Johnson K.G., Somersalo K., Sims T.N., Sumen C., et al. The immunological synapse. Annual Review of Immunology 2001, 19:375-396.
24. Brunkow M.E., Jeffery E.W., Hjerrild K.A., Paeper B., Clark L.B., Yasayko S.A., et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genetics 2001, 27:68-73.
25. Budde K., Sommerer C., Becker T., Asderakis A., Pietruck F., Grinyo J.M., et al. Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients. American Journal of Transplantation 2010, 10:571-581.
26. Burack W.R., Lee K.H., Holdorf A.D., Dustin M.L., Shaw A.S. Cutting edge: quantitative imaging of raft accumulation in the immunological synapse. Journal of Immunology 2002, 169:2837-2841.
27. Campi G., Varma R., Dustin M.L. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. Journal of Experimental Medicine 2005, 202:1031-1036.
28. Carrasco S., Merida I. Diacylglycerol-dependent binding recruits PKCθ and RasGRP1 C1 domains to specific subcellular localizations in living T lymphocytes. Molecular Biology of the Cell 2004, 15:2932-2942.
29. Cartwright N.G., Kashyap A.K., Schaefer B.C. An active kinase domain is required for retention of PKCθ at the T cell immunological synapse. Molecular Biology of the Cell 2011, 22:3491-3497.
30. Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawa U., Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. Journal of Biological Chemistry 1982, 257:7847-7851.
31. Cervino M.C., Lopez-Lago M.A., Vinuela J.E., Barja P. Specific inhibition of protein kinase Cβ expression by antisense RNA affects the activation of Jurkat T lymphoma cells. Journal of Biological Regulators Homeostatic Agents 2010, 24:273-285.
32. Chan A.C., Shaw A.S. Regulation of antigen receptor signal transduction by protein tyrosine kinases. Current Opinion in Immunology 1996, 8:394-401.
33. Chang J.D., Xu Y., Raychowdhury M.K., Ware J.A. 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 of Biological Chemistry 1993, 268:14208-14214.
34. Chuang H.C., Lan J.L., Chen D.Y., Yang C.Y., Chen Y.M., Li J.P., et al. The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells. Nature Immunology 2011, 12:1113-1118.
35. Cole D.C., Asselin M., Brennan A., Czerwinski R., Ellingboe J.W., Fitz L., et al. Identification, characterization and initial hit-to-lead optimization of a series of 4-arylamino-3-pyridinecarbonitrile as protein kinase C θ (PKCθ) inhibitors. Journal of Medicinal Chemistry 2008, 51:5958-5963.
36. Cooper J.D., Smyth D.J., Smiles A.M., Plagnol V., Walker N.M., Allen J.E., et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nature Genetics 2008, 40:1399-1401.
37. Coudronniere N., Villalba M., Englund N., Altman A. NF-κB activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-θ. Proceedings of the National Academy of Sciences of the United States of America 2000, 97:3394-3399.
38. Coussens L., Parker P.J., Rhee L., Yang-Feng T.L., Chen E., Waterfield M.D., et al. Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways. Science 1986, 233:859-866.
39. Curotto de Lafaille M.A., Lafaille J.J. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity 2009, 30:626-635.
40. Cywin C.L., Dahmann G., Prokopowicz A.S., Young E.R., Magolda R.L., Cardozo M.G., et al. Discovery of potent and selective PKC-θ inhibitors. Bioorganic & Medicinal Chemistry Letters 2007, 17:225-230.
41. Davis D.M., Chiu I., Fassett M., Cohen G.B., Mandelboim O., Strominger J.L. The human natural killer cell immune synapse. Proceedings of the National Academy of Sciences of the United States of America 1999, 96:15062-15067.
42. Debiec-Rychter M., Wasag B., Stul M., De Wever I., Van Oosterom A., Hagemeijer A., et al. Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. Journal of Pathology 2004, 202:430-438.
43. Dienz O., Hehner S.P., Droge W., Schmitz M.L. Synergistic activation of NF-κB by functional cooperation between Vav and PKCθ in T lymphocytes. Journal of Biological Chemistry 2000, 275:24547-24551.
44. Dienz O., Moller A., Strecker A., Stephan N., Krammer P.H., Droge W., et al. Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and phospholipase C γ1 are required for NF-κB activation and lipid raft recruitment of protein kinase C θ induced by T cell costimulation. Journal of Immunology 2003, 170:365-372.
45. Duensing A., Joseph N.E., Medeiros F., Smith F., Hornick J.L., Heinrich M.C., et al. Protein Kinase C θ (PKCθ) expression and constitutive activation in gastrointestinal stromal tumors (GISTs). Cancer Research 2004, 64:5127-5131.
46. Dustin M.L., Cooper J.A. The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling. Nature Immunology 2000, 1:23-29.
47. Dustin M.L., AllenImmunological Reviews P.M., Shaw A.S. Environmental control of immunological synapse formation and duration. Trends in Immunology 2001, 22:192-194.
48. Dustin M.L. Adhesive bond dynamics in contacts between T lymphocytes and glass-supported planar bilayers reconstituted with the immunoglobulin-related adhesion molecule CD58. Journal of Biological Chemistry 1997, 272:15782-15788.
49. Dustin M.L. T-cell activation through immunological synapses and kinapses. Immunological Reviews 2008, 221:77-89.
50. Erdel M., Baier-Bitterlich G., Duba C., Isakov N., Altman A., Utermann G., et al. Mapping of the human protein kinase C-θ (PRKCQ) gene locus to the short arm of chromosome 10 (10p15) by FISH. Genomics 1995, 25:595-597.
51. Evenou J.P., Wagner J., Zenke G., Brinkmann V., Wagner K., Kovarik J., et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. Journal of Pharmacology and Experimental Therapeutics 2009, 330:792-801.
52. Fang X., Wang R., Ma J., Ding Y., Shang W., Sun Z. Ameliorated ConA-induced hepatitis in the absence of PKC-θ. PLoS One 2012, 7:e31174.
53. Fathman C.G., Lineberry N.B. Molecular mechanisms of CD4+ T-cell anergy. Nature Reviews Immunology 2007, 7:599-609.
54. Freeley M., Volkov Y., Kelleher D., Long A. Stimulus-induced phosphorylation of PKC θ at the C-terminal hydrophobic-motif in human T lymphocytes. Biochemical and Biophysical Research 2005, 334:619-630.
55. Friman S., Arns W., Nashan B., Vincenti F., Banas B., Budde K., et al. Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. American Journal of Transplantation 2011, 11:1444-1455.
56. Fu G., Hu J., Niederberger-Magnenat N., Rybakin V., Casas J., Yachi P.P., et al. Protein kinase C η is required for T cell activation and homeostatic proliferation. Science Signaling 2011, 4. ra84.
57. Gambineri E., Torgerson T.R., Ochs H.D. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Current Opinion in Rheumatology 2003, 15:430-435.
58. Garaude J., Kaminski S., Charni S., Aguilo J.I., Jacquet C., Plays M., et al. Impaired anti-leukemic immune response in PKCθ-deficient mice. Molecular Immunology 2008, 45:3463-3469.
59. Genot E.M., Parker P.J., Cantrell D.A. Analysis of the role of protein kinase C-α, -ε, and -ζ in T cell activation. Journal of Biological Chemistry 1995, 270:9833-9839.
60. Ghosh S., Karin M. Missing pieces in the NF-κB puzzle. Cell 2002, 109(Suppl.):S81-S96.
61. Giannoni F., Lyon A.B., Wareing M.D., Dias P.B., Sarawar S.R. Protein kinase C θ is not essential for T-cell-mediated clearance of murine gammaherpesvirus 68. Journal of Virology 2005, 79:6808-6813.
62. Grakoui A., Bromley S.K., Sumen C., Davis M.M., Shaw A.S., Allen P.M., et al. The immunological synapse: a molecular machine controlling T cell activation. Science 1999, 285:221-227.
63. Griffin M.E., Marcucci M.J., Cline G.W., Bell K., Barucci N., Lee D., et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade. Diabetes 1999, 48:1270-1274.
64. Griffith J.W., O'Connor C., Bernard K., Town T., Goldstein D.R., Bucala R. Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host. Journal of Infectious Diseases 2007, 196:1553-1564.
65. Gruber T., Hermann-Kleiter N., Pfeifhofer-Obermair C., Lutz-Nicoladoni C., Thuille N., Letschka T., et al. PKC θ cooperates with PKC α in alloimmune responses of T cells in vivo. Molecular Immunology 2009, 46:2071-2079.
66. Gschwind A., Fischer O.M., Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Reviews Cancer 2004, 4:361-370.
67. Gupta S., Manicassamy S., Vasu C., Kumar A., Shang W., Sun Z. Differential requirement of PKC-θ in the development and function of natural regulatory T cells. Molecular Immunology 2008, 46:213-224.
68. Harder T., Rentero C., Zech T., Gaus K. Plasma membrane segregation during T cell activation: probing the order of domains. Current Opinion in Immunology 2007, 19:470-475.
69. Harding F.A., McArthur J.G., Gross J.A., Raulet D.H., Allison J.P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992, 356:607-609.
70. Hayashi K., Altman A. Protein kinase C θ (PKCθ): a key player in T cell life and death. Pharmacological Research 2007, 55:537-544.
71. Healy A.M., Izmailova E., Fitzgerald M., Walker R., Hattersley M., Silva M., et al. PKC-θ-deficient mice are protected from Th1-dependent antigen-induced arthritis. Journal of Immunology 2006, 177:1886-1893.
72. Heissmeyer V., Rao A. E3 ligases in T cell anergy-turning immune responses into tolerance. Science's STKE 2004, 2004. pe29.
73. Heissmeyer V., Macian F., Im S.H., Varma R., Feske S., Venuprasad K., et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunology 2004, 5:255-265.
74. Hirota S., Isozaki K., Moriyama Y., Hashimoto K., Nishida T., Ishiguro S., et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998, 279:577-580.
75. Hori S. c-Rel: a pioneer in directing regulatory T-cell lineage commitment?. European Journal of Immunology 2010, 40:664-667.
76. Huang J., Lo P.F., Zal T., Gascoigne N.R., Smith B.A., Levin S.D., et al. CD28 plays a critical role in the segregation of PKCθ within the immunologic synapse. Proceedings of the National Academy of Sciences of the United States of America 2002, 99:9369-9373.
77. Hug H., Sarre T.F. Protein kinase C isoenzymes: divergence in signal transduction?. Biochemical Journal 1993, 291(Pt 2):329-343.
78. Inoue M., Kishimoto A., Takai Y., Nishizuka Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain. Journal of Biological Chemistry 1977, 252:7610-7616.
79. Isakov N., Altman A. Tumor promoters in conjunction with calcium ionophores mimic antigenic stimulation by reactivation of alloantigen-primed murine T lymphocytes. Journal of Immunology 1985, 135:3674-3680.
80. Isakov N., Altman A. PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors. Frontiers in Immunology 2012, 3:273.
81. Itani S.I., Zhou Q., Pories W.J., MacDonald K.G., Dohm G.L. Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes 2000, 49:1353-1358.
82. Jang M.S., Pan F., Erickson L.M., Fisniku O., Crews G., Wynn C., et al. A blocking anti-CD28-specific antibody induces long-term heart allograft survival by suppression of the PKC theta-JNK signal pathway. Transplantation 2008, 85:1051-1055.
83. Jenkins M.K., Chen C.A., Jung G., Mueller D.L., Schwartz R.H. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. Journal of Immunology 1990, 144:16-22.
84. Josefowicz S.Z., Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009, 30:616-625.
85. Josefowicz S.Z., Lu L.F., Rudensky A.Y. Regulatory T cells: mechanisms of differentiation and function. Annual Review of Immunology 2012, 30:531-564.
86. Kabouridis P.S., Jury E.C. Lipid rafts and T-lymphocyte function: implications for autoimmunity. FEBS Letters 2008, 582:3711-3718.
87. Kaibuchi K., Takai Y., Nishizuka Y. Protein kinase C and calcium ion in mitogenic response of macrophage-depleted human peripheral lymphocytes. Journal of Biological Chemistry 1985, 260:1366-1369.
88. Kamo N., Shen X.D., Ke B., Busuttil R.W., Kupiec-Weglinski J.W. Sotrastaurin, a protein kinase C inhibitor, ameliorates ischemia and reperfusion injury in rat orthotropic liver transplantation. American Journal of Transplantation 2011, 11:2499-2507.
89. Kane L.P., Lin J., Weiss A. Signal transduction by the TCR for antigen. Current Opinion in Immunology 2000, 12:242-249.
90. Kang G.H., Kim K.M., Park C.K., Kang D.Y. PKC-θ expression in Ewing sarcoma/primitive neuroectodermal tumour and malignant peripheral nerve sheath tumour. Histopathology 2009, 55:368-369.
91. Kenworthy A.K. Have we become overly reliant on lipid rafts? Talking Point on the involvement of lipid rafts in T-cell activation. EMBO Reports 2008, 9:531-535.
92. Kikkawa U., Takai Y., Tanaka Y., Miyake R., Nishizuka Y. Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters. Journal of Biological Chemistry 1983, 258:11442-11445.
93. Kim J.K., Fillmore J.J., Sunshine M.J., Albrecht B., Higashimori T., Kim D.W., et al. PKC-θ knockout mice are protected from fat-induced insulin resistance. Journal of Clinical Investigation 2004, 114:823-827.
94. Kong K.F., Altman A. In and out of the bull's eye: PKCs at the immunological synapse 2013, Trends in Immunology, in press.
95. Kong K.F., Yokosuka T., Canonigo-Balancio A.J., Isakov N., Saito T., Altman A. A motif in the V3 domain of the kinase PKC-θ determines its localization in the immunological synapse and functions in T cells via association with CD28. Nature Immunology 2011, 12:1105-1112.
96. Kontzias A., Laurence A., Gadina M., O'Shea J.J. Kinase inhibitors in the treatment of immune-mediated disease. F1000 Medicine Reports 2012, 4:5.
97. Krzewski K., Chen X., Orange J.S., Strominger J.L. Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. Journal of Cell Biology 2006, 173:121-132.
98. Kwon M.J., Ma J., Ding Y., Wang R., Sun Z. Protein kinase C-θ promotes Th17 differentiation via upregulation of Stat3. Journal of Immunology 2012, 188:5887-5897.
99. Lamba V., Ghosh I. New directions in targeting protein kinases: focusing upon true allosteric and bivalent inhibitors. Current Pharmaceutical Design 2012, 18:2936-2945.
100. Lee K.H., Dinner A.R., Tu C., Campi G., Raychaudhuri S., Varma R., et al. The immunological synapse balances T cell receptor signaling and degradation. Science 2003, 302:1218-1222.
101. Lee H.E., Kim M.A., Lee H.S., Lee B.L., Kim W.H. Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C θ immunostaining. Journal of Clinical Pathology 2008, 61:722-729.
102. Letschka T., Kollmann V., Pfeifhofer-Obermair C., Lutz-Nicoladoni C., Obermair G.J., Fresser F., et al. PKC-θ selectively controls the adhesion-stimulating molecule Rap1. Blood 2008, 112:4617-4627.
103. Li Y., Hu J., Vita R., Sun B., Tabata H., Altman A. SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway. EMBO Journal 2004, 23:1112-1122.
104. Lin X., Wang D. The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling. Seminars in Immunology 2004, 16:429-435.
105. Lin X., O'Mahony A., Mu Y., Geleziunas R., Greene W.C. Protein kinase C-θ participates in NF-κB activation induced by CD3-CD28 costimulation through selective activation of IκB kinase β. Molecular and Cellular Biology 2000, 20:2933-2940.
106. Liu Y., Witte S., Liu Y.C., Doyle M., Elly C., Altman A. Regulation of protein kinase Cθ function during T cell activation by Lck-mediated tyrosine phosphorylation. Journal of Biological Chemistry 2000, 275:3603-3609.
107. Liu Y., Graham C., Parravicini V., Brown M.J., Rivera J., Shaw S. Protein kinase C θ is expressed in mast cells and is functionally involved in Fcepsilon receptor I signaling. Journal of Leukocyte Biology 2001, 69:831-840.
108. Liu Y., Graham C., Li A., Fisher R.J., Shaw S. Phosphorylation of the protein kinase C-θ activation loop and hydrophobic motif regulates its kinase activity, but only activation loop phosphorylation is critical to in vivo nuclear-factor-κB induction. Biochemical Journal 2002, 361(Pt 2):255-265.
109. Long A., Kelleher D., Lynch S., Volkov Y. Cutting edge: protein kinase C β expression is critical for export of IL-2 from T cells. Journal of Immunology 2001, 167:636-640.
110. Ma J., Ding Y., Fang X., Wang R., Sun Z. Protein kinase C-θ inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. Journal of Immunology 2012, 188:5337-5347.
111. Macian F., Garcia-Cozar F., Im S.H., Horton H.F., Byrne M.C., Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 2002, 109:719-731.
112. Macian F., Im S.H., Garcia-Cozar F.J., Rao A. T-cell anergy. Current Opinion in Immunology 2004, 16:209-216.
113. Manicassamy S., Gupta S., Huang Z., Sun Z. Protein kinase C-θ-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL. Journal of Immunology 2006, 176:6709-6716.
114. Manicassamy S., Sadim M., Ye R.D., Sun Z. Differential roles of PKC-θ in the regulation of intracellular calcium concentration in primary T cells. Journal of Molecular Biology 2006, 355:347-359.
115. Manicassamy S., Yin D., Zhang Z., Molinero L.L., Alegre M.L., Sun Z. A critical role for protein kinase C-θ-mediated T cell survival in cardiac allograft rejection. Journal of Immunology 2008, 181:513-520.
116. Marsland B.J., Soos T.J., Spath G., Littman D.R., Kopf M. Protein kinase C θ is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. Journal of Experimental Medicine 2004, 200:181-189.
117. Marsland B.J., Nembrini C., Schmitz N., Abel B., Krautwald S., Bachmann M.F., et al. Innate signals compensate for the absence of PKC-θ during in vivo CD8+ T cell effector and memory responses. Proceedings of the National Academy of Sciences of the United States of America 2005, 102:14374-14379.
118. Marsland B.J., Nembrini C., Grun K., Reissmann R., Kurrer M., Leipner C., et al. TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-θ signaling and promote autoimmune myocarditis. Journal of Immunology 2007, 178:3466-3473.
119. Martin P., Villares R., Rodriguez-Mascarenhas S., Zaballos A., Leitges M., Kovac J., et al. Control of T helper 2 cell function and allergic airway inflammation by PKCζ. Proceedings of the National Academy of Sciences of the United States of America 2005, 102:9866-9871.
120. Matz M., Weber U., Mashreghi M.F., Lorkowski C., Ladhoff J., Kramer S., et al. Effects of the new immunosuppressive agent AEB071 on human immune cells. Nephrology Dialysis Transplantation 2010, 25:2159-2167.
121. Meller N., Altman A., Isakov N. New perspectives on PKCθ, a member of the novel subfamily of protein kinase C. Stem Cells 1998, 16:178-192.
122. Meller N., Elitzur Y., Isakov N. Protein kinase C-θ (PKCθ) distribution analysis in hematopoietic cells: proliferating T cells exhibit high proportions of PKCtheta in the particulate fraction. Cellular Immunology 1999, 193:185-193.
123. Mellor H., Parker P.J. The extended protein kinase C superfamily. Biochemical Journal 1998, 332(Pt 2):281-292.
124. Mirandola P., Gobbi G., Masselli E., Micheloni C., Di Marcantonio D., Queirolo V., et al. Protein kinase Cε regulates proliferation and cell sensitivity to TGF-1β of CD4+ T lymphocytes: implications for Hashimoto thyroiditis. Journal of Immunology 2011, 187:4721-4732.
125. Mohib K., AlKhamees B., Zein H.S., Allan D., Wang L. Embryonic stem cell-derived factors inhibit T effector activation and induce T regulatory cells by suppressing PKC-θ activation. PLoS One 2012, 7:e32420.
126. Monaco G., Pignata C., Rossi E., Mascellaro O., Cocozza S., Ciccimarra F. DiGeorge anomaly associated with 10p deletion. American Journal of Medical Genetics 1991, 39:215-216.
127. Monks C.R., Kupfer H., Tamir I., Barlow A., Kupfer A. Selective modulation of protein kinase C-θ during T-cell activation. Nature 1997, 385:83-86.
128. Monks C.R., Freiberg B.A., Kupfer H., Sciaky N., Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 1998, 395:82-86.
129. Morley S.C., Weber K.S., Kao H., Allen P.M. Protein kinase C-θ is required for efficient positive selection. Journal of Immunology 2008, 181:4696-4708.
130. Mosyak L., Xu Z., Joseph-McCarthy D., Brooijmans N., Somers W., Chaudhary D. Structure-based optimization of PKCθ inhibitors. Biochemical Society Transactions 2007, 35(Pt 5):1027-1031.
131. Motegi A., Sakurai S., Nakayama H., Sano T., Oyama T., Nakajima T. PKC θ, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors. Pathology International 2005, 55:106-112.
132. Newton A.C. Regulation of protein kinase C. Current Opinion in Cell Biology 1997, 9:161-167.
133. Niedel J.E., Kuhn L.J., Vandenbark G.R. Phorbol diester receptor copurifies with protein kinase C. Proceedings of the National Academy of Sciences of the United States of America 1983, 80:36-40.
134. Nishanth G., Sakowicz-Burkiewicz M., Handel U., Kliche S., Wang X., Naumann M., et al. Protective Toxoplasma gondii-specific T-cell responses require T-cell-specific expression of protein kinase C-θ. Infection and Immunity 2010, 78:3454-3464.
135. Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB Journal 1995, 9:484-496.
136. Ohayon A., Golenser J., Sinay R., Tamir A., Altman A., Pollack Y., et al. Protein kinase C θ deficiency increases resistance of C57BL/6J mice to Plasmodium berghei infection-induced cerebral malaria. Infection and Immunity 2010, 78:4195-4205.
137. Osada S., Mizuno K., Saido T.C., Suzuki K., Kuroki T., Ohno S. A new member of the protein kinase C family, nPKC θ, predominantly expressed in skeletal muscle. Molecular and Cellular Biology 1992, 12:3930-3938.
138. Ou W.B., Zhu M.J., Demetri G.D., Fletcher C.D., Fletcher J.A. Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors. Oncogene 2008, 27:5624-5634.
139. -/- mice stimulated with interleukin-12 are deficient in production of interferon-γ. Journal of Leukocyte Biology 2008, 83:1267-1276.
140. Pardo J., Buferne M., Martinez-Lorenzo M.J., Naval J., Schmitt-Verhulst A.M., Boyer C., et al. Differential implication of protein kinase C isoforms in cytotoxic T lymphocyte degranulation and TCR-induced Fas ligand expression. International Immunology 2003, 15:1441-1450.
141. Parker P.J., Coussens L., Totty N., Rhee L., Young S., Chen E., et al. The complete primary structure of protein kinase C-the major phorbol ester receptor. Science 1986, 233:853-859.
142. Passalacqua M., Patrone M., Sparatore B., Melloni E., Pontremoli S. Protein kinase C-θ is specifically localized on centrosomes and kinetochores in mitotic cells. Biochemical Journal 1999, 337(Pt 1):113-118.
143. 2+ mobilization and NFAT cell activation in primary mouse T cells. Journal of Experimental Medicine 2003, 197:1525-1535.
144. -/- mice. Journal of Immunology 2006, 176:6004-6011.
145. Pfeifhofer-Obermair C., Thuille N., Baier G. Involvement of distinct PKC gene products in T cell functions. Frontiers in Immunology 2012, 3:220.
146. Praveen K., Zheng Y., Rivas F., Gajewski T.F. Protein kinase Cθ focusing at the cSMAC is a consequence rather than cause of TCR signaling and is dependent on the MEK/ERK pathway. Journal of Immunology 2009, 182:6022-6030.
147. Quann E.J., Liu X., Altan-Bonnet G., Huse M. A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells. Nature Immunology 2011, 12:647-654.
148. Quittau-Prevostel C., Delaunay N., Collazos A., Vallentin A., Joubert D. Targeting of PKCα and θ in the pituitary: a highly regulated mechanism involving a GD(E)E motif of the V3 region. Journal of Cell Science 2004, 117(Pt 1):63-72.
149. Ramagopalan S.V., Heger A., Berlanga A.J., Maugeri N.J., Lincoln M.R., Burrell A., et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Research 2010, 20:1352-1360.
150. Raychaudhuri S., Remmers E.F., Lee A.T., Hackett R., Guiducci C., Burtt N.P., et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nature Genetics 2008, 40:1216-1223.
151. Reddy M.V., Wang H., Liu S., Bode B., Reed J.C., Steed R.D., et al. Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population. Genes and Immunity 2011, 12:208-212.
152. Rudensky A.Y. Regulatory T cells and Foxp3. Immunological Reviews 2011, 241:260-268.
153. Saibil S.D., Deenick E.K., Ohashi P.S. The sound of silence: modulating anergy in T lymphocytes. Current Opinion in Immunology 2007, 19:658-664.
154. Saibil S.D., Jones R.G., Deenick E.K., Liadis N., Elford A.R., Vainberg M.G., et al. CD4+ and CD8+ T cell survival is regulated differentially by protein kinase Cθ, c-Rel, and protein kinase B. Journal of Immunology 2007, 178:2932-2939.
155. Saito T., Yokosuka T. Immunological synapse and microclusters: the site for recognition and activation of T cells. Current Opinion in Immunology 2006, 18:305-313.
156. Sakaguchi S., Yamaguchi T., Nomura T., Ono M. Regulatory T cells and immune tolerance. Cell 2008, 133:775-787.
157. Salek-Ardakani S., So T., Halteman B.S., Altman A., Croft M. Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase C θ. Journal of Immunology 2004, 173:6440-6447.
158. Salek-Ardakani S., So T., Halteman B.S., Altman A., Croft M. Protein kinase Cθ controls Th1 cells in experimental autoimmune encephalomyelitis. Journal of Immunology 2005, 175:7635-7641.
159. Samelson L.E. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annual Review of Immunology 2002, 20:371-394.
160. Sarris M., Andersen K.G., Randow F., Mayr L., Betz A.G. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 2008, 28:402-413.
161. Schmidt-Supprian M., Tian J., Grant E.P., Pasparakis M., Maehr R., Ovaa H., et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proceedings of the National Academy of Sciences of the United States of America 2004, 101:4566-4571.
162. Schwartz R.H. T cell anergy. Annual Review of Immunology 2003, 21:305-334.
163. Seco J., Ferrer-Costa C., Campanera J.M., Soliva R., Barril X. Allosteric regulation of PKCθ: understanding multistep phosphorylation and priming by ligands in AGC kinases. Proteins 2012, 80:269-280.
164. Sedwick C.E., Morgan M.M., Jusino L., Cannon J.L., Miller J., Burkhardt J.K. TCR, LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization. Journal of Immunology 1999, 162:1367-1375.
165. Serra C., Federici M., Buongiorno A., Senni M.I., Morelli S., Segratella E., et al. Transgenic mice with dominant negative PKC-θ in skeletal muscle: a new model of insulin resistance and obesity. Journal of Cell Physiology 2003, 196:89-97.
166. Shaulian E., Karin M. AP-1 as a regulator of cell life and death. Nature Cell Biology 2002, 4:E131-E136.
167. Sims T.N., Soos T.J., Xenias H.S., Dubin-Thaler B., Hofman J.M., Waite J.C., et al. Opposing effects of PKCθ and WASp on symmetry breaking and relocation of the immunological synapse. Cell 2007, 129:773-785.
168. Singleton K.L., Gosh M., Dandekar R.D., Au-Yeung B.B., Ksionda O., Tybulewicz V.L., et al. Itk controls the spatiotemporal organization of T cell activation. Science Signaling 2011, 4. ra66.
169. Skvara H., Dawid M., Kleyn E., Wolff B., Meingassner J.G., Knight H., et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. Journal of Clinical Investigation 2008, 118:3151-3159.
170. Spitaler M., Emslie E., Wood C.D., Cantrell D. Diacylglycerol and protein kinase D localization during T lymphocyte activation. Immunity 2006, 24:535-546.
171. Stahl E.A., Raychaudhuri S., Remmers E.F., Xie G., Eyre S., Thomson B.P., et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature Genetics 2010, 42:508-514.
172. Steinberg S.F. Structural basis of protein kinase C isoform function. Physiological Reviews 2008, 88:1341-1378.
173. Stevens L., Htut T.M., White D., Li X., Hanidu A., Stearns C., et al. Involvement of GATA3 in Protein Kinase C θ-induced Th2 cytokine expression. European Journal of Immunology 2006, 36:3305-3314.
174. Steward-Tharp S.M., Song Y.J., Siegel R.M., O'Shea J.J. New insights into T cell biology and T cell-directed therapy for autoimmunity, inflammation, and immunosuppression. Annals of the New York Academy of Sciences 2010, 1183:123-148.
175. Sun Z., Arendt C.W., Ellmeier W., Schaeffer E.M., Sunshine M.J., Gandhi L., et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 2000, 404:402-407.
176. Sun Z. Intervention of PKC-theta as an immunosuppressive regimen. Frontiers in Immunology 2012, 3:225.
177. Sutcliffe E.L., Bunting K.L., He Y.Q., Li J., Phetsouphanh C., Seddiki N., et al. Chromatin-associated protein kinase C-θ regulates an inducible gene expression program and microRNAs in human T lymphocytes. Molecular Cell 2011, 41:704-719.
178. Szamel M., Appel A., Schwinzer R., Resch K. Different protein kinase C isoenzymes regulate IL-2 receptor expression or IL-2 synthesis in human lymphocytes stimulated via the TCR. Journal of Immunology 1998, 160:2207-2214.
179. Takai Y., Kishimoto A., Iwasa Y., Kawahara Y., Mori T., Nishizuka Y. Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids. Journal of Biological Chemistry 1979, 254:3692-3695.
180. Tan S.L., Zhao J., Bi C., Chen X.C., Hepburn D.L., Wang J., et al. Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase C θ-deficient mice. Journal of Immunology 2006, 176:2872-2879.
181. Tassi I., Cella M., Presti R., Colucci A., Gilfillan S., Littman D.R., et al. NK cell-activating receptors require PKC-θ for sustained signaling, transcriptional activation, and IFN-γ secretion. Blood 2008, 112:4109-4116.
182. Thuille N., Heit I., Fresser F., Krumbock N., Bauer B., Leuthaeusser S., et al. Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCθ in T lymphocytes. EMBO Journal 2005, 24:3869-3880.
183. Touraine J.L., Hadden J.W., Touraine F., Hadden E.M., Estensen R., Good R.A. Phorbol myristate acetate: a mitogen selective for a T-lymphocyte subpopulation. Journal of Experimental Medicine 1977, 145:460-465.
184. Truneh A., Albert F., Golstein P., Schmitt-Verhulst A.M. Calcium ionophore plus phorbol ester can substitute for antigen in the induction of cytolytic T lymphocytes from specifically primed precursors. Journal of Immunology 1985, 135:2262-2267.
185. Truneh A., Albert F., Golstein P., Schmitt-Verhulst A.M. Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester. Nature 1985, 313:318-320.
186. Tseng S.Y., Liu M., Dustin M.L. CD80 cytoplasmic domain controls localization of CD28, CTLA-4, and protein kinase Cθ in the immunological synapse. Journal of Immunology 2005, 175:7829-7836.
187. Tseng S.Y., Waite J.C., Liu M., Vardhana S., Dustin M.L. T cell-dendritic cell immunological synapses contain TCR-dependent CD28-CD80 clusters that recruit protein kinase C theta. Journal of Immunology 2008, 181:4852-4863.
188. Valenzuela J.O., Iclozan C., Hossain M.S., Prlic M., Hopewell E., Bronk C.C., et al. PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice. Journal of Clinical Investigation 2009, 119:3774-3786.
189. Vardhana S., Choudhuri K., Varma R., Dustin M.L. Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster. Immunity 2010, 32:531-540.
190. Varma R., Campi G., Yokosuka T., Saito T., Dustin M.L. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 2006, 25:117-127.
191. Verma R.S., Macera M.J., Krishnamurthy M., Abramson J., Kapelner S., Dosik H. Chromosomal abnormalities in adult T-cell leukemia/lymphoma (ATL). A report of six cases with review of the literature. Journal of Cancer Research and Clinical Oncology 1987, 113:192-196.
192. Villalba M., Altman A. Protein kinase C-θ (PKCθ), an example of a drug target for therapeutic intervention with human T cell leukemias. Current Cancer Drug Targets 2002, 2:125-134.
193. Villalba M., Kasibhatla S., Genestier L., Mahboubi A., Green D.R., Altman A. Protein kinase Cθ cooperates with calcineurin to induce Fas ligand expression during activation-induced T cell death. Journal of Immunology 1999, 163:5813-5819.
194. Villalba M., Coudronniere N., Deckert M., Teixeiro E., Mas P., Altman A. A novel functional interaction between Vav and PKCθ is required for TCR-induced T cell activation. Immunity 2000, 12:151-160.
195. Villalba M., Bushway P., Altman A. PKCθ mediates a selective T cell survival signal via phosphorylation of BAD. Journal of Immunology 2001, 166:5955-5963.
196. Villalba M., Bi K., Hu J., Altman Y., Bushway P., Reits E., et al. Translocation of PKCθ in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. Journal of Cell Biology 2002, 157:253-263.
197. Villunger A., Ghaffari-Tabrizi N., Tinhofer I., Krumbock N., Bauer B., Schneider T., et al. Synergistic action of protein kinase C θ and calcineurin is sufficient for Fas ligand expression and induction of a crmA-sensitive apoptosis pathway in Jurkat T cells. European Journal of Immunology 1999, 29:3549-3561.
198. Volkov Y., Long A., Kelleher D. Inside the crawling T cell: leukocyte function-associated antigen-1 cross-linking is associated with microtubule-directed translocation of protein kinase C isoenzymes βI and δ. Journal of Immunology 1998, 161:6487-6495.
199. Volkov Y., Long A., McGrath S., Ni Eidhin D., Kelleher D. Crucial importance of PKC-βI in LFA-1-mediated locomotion of activated T cells. Nature Immunology 2001, 2:508-514.
200. von Essen M., Nielsen M.W., Bonefeld C.M., Boding L., Larsen J.M., Leitges M., et al. Protein kinase C (PKC) α and PKC are the major PKC isotypes involved in TCR down-regulation. Journal of Immunology 2006, 176:7502-7510.
201. Vyas Y.M., Mehta K.M., Morgan M., Maniar H., Butros L., Jung S., et al. Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. Journal of Immunology 2001, 167:4358-4367.
202. Wang D., You Y., Case S.M., McAllister-Lucas L.M., Wang L., DiStefano P.S., et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nature Immunology 2002, 3:830-835.
203. Wang X., Chuang H.C., Li J.P., Tan T.H. Regulation of PKC-θ function by phosphorylation in T cell receptor signaling. Frontiers in Immunology 2012, 3:197.
204. Wange R.L. LAT, the linker for activation of T cells: a bridge between T cell-specific and general signaling pathways. Science STKE 2000, 63. RE1.
205. Weckbecker G., Pally C., Beerli C., Burkhart C., Wieczorek G., Metzler B., et al. Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720. Transplant International 2010, 23:543-552.
206. Weil R., Israel A. T-cell-receptor- and B-cell-receptor-mediated activation of NF-κB in lymphocytes. Current Opinion in Immunology 2004, 16:374-381.
207. Xu Z.B., Chaudhary D., Olland S., Wolfrom S., Czerwinski R., Malakian K., et al. Catalytic domain crystal structure of protein kinase C-θ (PKCθ). Journal of Biological Chemistry 2004, 279:50401-50409.
208. Yarovinsky F., Zhang D., Andersen J.F., Bannenberg G.L., Serhan C.N., Hayden M.S., et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 2005, 308:1626-1629.
209. Yokosuka T., Sakata-Sogawa K., Kobayashi W., Hiroshima M., Hashimoto-Tane A., Tokunaga M., et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nature Immunology 2005, 6:1253-1262.
210. Yokosuka T., Kobayashi W., Sakata-Sogawa K., Takamatsu M., Hashimoto-Tane A., Dustin M.L., et al. Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters and protein kinase C θ translocation. Immunity 2008, 29:589-601.
211. Yokosuka T., Kobayashi W., Takamatsu M., Sakata-Sogawa K., Zeng H., Hashimoto-Tane A., et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 2010, 33:326-339.
212. Zanin-Zhorov A., Ding Y., Kumari S., Attur M., Hippen K.L., Brown M., et al. Protein kinase C-θ mediates negative feedback on regulatory T cell function. Science 2010, 328:372-376.
213. Zanin-Zhorov A., Dustin M.L., Blazar B.R. PKC-θ function at the immunological synapse: prospects for therapeutic targeting. Trends in Immunology 2011, 32:358-363.
214. Zhernakova A., Stahl E.A., Trynka G., Raychaudhuri S., Festen E.A., Franke L., et al. PLoS Genetics 2011, 7:e1002004.