1932

Abstract

The protein kinase C (PKC) family, discovered in the late 1970s, is composed of at least 10 serine/threonine kinases, divided into three groups based on their molecular architecture and cofactor requirements. PKC enzymes have been conserved throughout evolution and are expressed in virtually all cell types; they represent critical signal transducers regulating cell activation, differentiation, proliferation, death, and effector functions. PKC family members play important roles in a diverse array of hematopoietic and immune responses. This review covers the discovery and history of this enzyme family, discusses the roles of PKC enzymes in the development and effector functions of major hematopoietic and immune cell types, and points out gaps in our knowledge, which should ignite interest and further exploration, ultimately leading to better understanding of this enzyme family and, above all, its role in the many facets of the immune system.

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2016-05-20
2024-06-14
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Literature Cited

  1. Berenblum I. 1.  1941. The mechanism of carcinogenesis—a study of the significance of cocarcinogenic action and related phenomena. Cancer Res. 1:807–14 [Google Scholar]
  2. Berenblum I. 2.  1941. The cocarcinogenic action of croton resin. Cancer Res. 1:44–48 [Google Scholar]
  3. Berenblum I. 3.  1947. Cocarcinogenesis. Br. Med. Bull. 4:343–45 [Google Scholar]
  4. Hecker E. 4.  1968. Cocarcinogenic principles from seed oil of Croton tiglium and from other Euphorbiaceae. Cancer Res. 28:2338–49 [Google Scholar]
  5. Blumberg PM, Delclos KB, Dunphy WG, Jaken S. 5.  1982. Specific binding of phorbol ester tumor promoters to mouse tissues and cultured cells. Carcinog. Compr. Surv. 7:519–35 [Google Scholar]
  6. Blumberg PM. 6.  1988. Protein kinase-C as the receptor for the phorbol ester tumor promoters: sixth Rhoads Memorial Award lecture. Cancer Res. 48:1–8 [Google Scholar]
  7. Delclos KB, Nagle DS, Blumberg PM. 7.  1980. Specific binding of phorbol ester tumor promoters to mouse skin. Cell 19:1025–32 [Google Scholar]
  8. Ashendel CL, Boutwell RK. 8.  1981. Direct measurement of specific binding of highly lipophilic phorbol diester to mouse epidermal membranes using cold acetone. Biochem. Biophys. Res. Commun. 99:543–49 [Google Scholar]
  9. Kishimoto A, Takai Y, Nishizuka Y. 9.  1977. Activation of glycogen phosphorylase kinase by a calcium-activated, cyclic nucleotide–independent protein kinase system. J. Biol. Chem. 252:7449–52 [Google Scholar]
  10. Takai Y, Kishimoto A, Kikkawa U, Mori T, Nishizuka Y. 10.  1979. Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid-dependent protein kinase system. Biochem. Biophys. Res. Commun. 91:1218–24 [Google Scholar]
  11. Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. 11.  1982. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257:7847–51 [Google Scholar]
  12. Nishizuka Y. 12.  1984. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308:693–98 [Google Scholar]
  13. Horowitz AD, Greenebaum E, Weinstein IB. 13.  1981. Identification of receptors for phorbol ester tumor promoters in intact mammalian cells and of an inhibitor of receptor binding in biologic fluids. PNAS 78:2315–19 [Google Scholar]
  14. Dunn JA, Blumberg PM. 14.  1983. Specific binding of [20-3H]12-deoxyphorbol 13-isobutyrate to phorbol ester receptor subclasses in mouse skin particulate preparations. Cancer Res. 43:4632–37 [Google Scholar]
  15. Coussens L, Parker PJ, Rhee L, Yang-Feng TL, Chen E. 15.  et al. 1986. Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways. Science 233:859–66 [Google Scholar]
  16. Parker PJ, Coussens L, Totty N, Rhee L, Young S. 16.  et al. 1986. The complete primary structure of protein kinase C—the major phorbol ester receptor. Science 233:853–59 [Google Scholar]
  17. Ohno S, Kawasaki H, Imajoh S, Suzuki K, Inagaki M. 17.  et al. 1987. Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325:161–66 [Google Scholar]
  18. Ono Y, Kikkawa U, Ogita K, Fujii T, Kurokawa T. 18.  et al. 1987. Expression and properties of two types of protein kinase C: alternative splicing from a single gene. Science 236:1116–20 [Google Scholar]
  19. Ono Y, Fujii T, Ogita K, Kikkawa U, Igarashi K, Nishizuka Y. 19.  1988. The structure, expression, and properties of additional members of the protein kinase C family. J. Biol. Chem. 263:6927–32 [Google Scholar]
  20. Ohno S, Akita Y, Konno Y, Imajoh S, Suzuki K. 20.  1988. A novel phorbol ester receptor/protein kinase, nPKC, distantly related to the protein kinase C family. Cell 53:731–41 [Google Scholar]
  21. Osada S, Mizuno K, Saido TC, Akita Y, Suzuki K. 21.  et al. 1990. A phorbol ester receptor/protein kinase, nPKCη, a new member of the protein kinase C family predominantly expressed in lung and skin. J. Biol. Chem. 265:22434–40 [Google Scholar]
  22. Bacher N, Zisman Y, Berent E, Livneh E. 22.  1991. Isolation and characterization of PKC-L, a new member of the protein kinase C–related gene family specifically expressed in lung, skin, and heart. Mol. Cell. Biol. 11:126–33 [Google Scholar]
  23. Baier G, Telford D, Giampa L, Coggeshall KM, Baier-Bitterlich G. 23.  et al. 1993. Molecular cloning and characterization of PKCθ, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells. J. Biol. Chem. 268:4997–5004 [Google Scholar]
  24. Osada S, Mizuno K, Saido TC, Suzuki K, Kuroki T, Ohno S. 24.  1992. A new member of the protein kinase C family, nPKCθ, predominantly expressed in skeletal muscle. Mol. Cell. Biol. 12:3930–38 [Google Scholar]
  25. Chang JD, Xu Y, Raychowdhury MK, Ware JA. 25.  1993. 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. J. Biol. Chem. 268:14208–14 [Google Scholar]
  26. Ono Y, Fujii T, Ogita K, Kikkawa U, Igarashi K, Nishizuka Y. 26.  1989. Protein kinase C ζ subspecies from rat brain: its structure, expression, and properties. PNAS 86:3099–103 [Google Scholar]
  27. Selbie LA, Schmitz-Peiffer C, Sheng Y, Biden TJ. 27.  1993. Molecular cloning and characterization of PKCι, an atypical isoform of protein kinase C derived from insulin-secreting cells. J. Biol. Chem. 268:24296–302 [Google Scholar]
  28. Akimoto K, Mizuno K, Osada S, Hirai S, Tanuma S. 28.  et al. 1994. A new member of the third class in the protein kinase C family, PKCλ, expressed dominantly in an undifferentiated mouse embryonal carcinoma cell line and also in many tissues and cells. J. Biol. Chem. 269:12677–83 [Google Scholar]
  29. Seita J, Weissman IL. 29.  2010. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip. Rev. Syst. Biol. Med. 2:640–53 [Google Scholar]
  30. Yamashita YM, Yuan H, Cheng J, Hunt AJ. 30.  2010. Polarity in stem cell division: asymmetric stem cell division in tissue homeostasis. Cold Spring Harb. Perspect. Biol. 2a001313 [Google Scholar]
  31. Sengupta A, Duran A, Ishikawa E, Florian MC, Dunn SK. 31.  et al. 2011. Atypical protein kinase C (aPKCζ and aPKCλ) is dispensable for mammalian hematopoietic stem cell activity and blood formation. PNAS 108:9957–62 [Google Scholar]
  32. Morrison SJ, Weissman IL. 32.  1994. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1:661–73 [Google Scholar]
  33. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. 33.  2002. A stem cell molecular signature. Science 298:601–4 [Google Scholar]
  34. Hazen AL, Diks SH, Wahle JA, Fuhler GM, Peppelenbosch MP, Kerr WG. 34.  2011. Major remodelling of the murine stem cell kinome following differentiation in the hematopoietic compartment. J. Proteome Res. 10:3542–50 [Google Scholar]
  35. Altman A, Kong KF. 35.  2014. Protein kinase C inhibitors for immune disorders. Drug Discov. Today 19:1217–21 [Google Scholar]
  36. Kaushansky K. 36.  2006. Lineage-specific hematopoietic growth factors. N. Engl. J. Med. 354:2034–45 [Google Scholar]
  37. Zamai L, Secchiero P, Pierpaoli S, Bassini A, Papa S. 37.  et al. 2000. TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis. Blood 95:3716–24 [Google Scholar]
  38. Bassini A, Zauli G, Migliaccio G, Migliaccio AR, Pascuccio M. 38.  et al. 1999. Lineage-restricted expression of protein kinase C isoforms in hematopoiesis. Blood 93:1178–88 [Google Scholar]
  39. Mirandola P, Gobbi G, Ponti C, Sponzilli I, Cocco L, Vitale M. 39.  2006. PKCε controls protection against TRAIL in erythroid progenitors. Blood 107:508–13 [Google Scholar]
  40. Zucker MB, Troll W, Belman S. 40.  1974. The tumor-promoter phorbol ester (12-O-tetradecanoyl-phorbol-13-acetate), a potent aggregating agent for blood platelets. J. Cell Biol. 60:325–36 [Google Scholar]
  41. White JG, Rao GH, Estensen RD. 41.  1974. Investigation of the release reaction in platelets exposed to phorbol myristate acetate. Am. J. Pathol. 75:301–14 [Google Scholar]
  42. Kawahara Y, Takai Y, Minakuchi R, Sano K, Nishizuka Y. 42.  1980. Phospholipid turnover as a possible transmembrane signal for protein phosphorylation during human platelet activation by thrombin. Biochem. Biophys. Res. Commun. 97:309–17 [Google Scholar]
  43. Gobbi G, Mirandola P, Sponzilli I, Micheloni C, Malinverno C. 43.  et al. 2007. Timing and expression level of protein kinase Cε regulate the megakaryocytic differentiation of human CD34 cells. Stem Cells 25:2322–29 [Google Scholar]
  44. Racke FK, Wang D, Zaidi Z, Kelley J, Visvader J. 44.  et al. 2001. A potential role for protein kinase C-ε in regulating megakaryocytic lineage commitment. J. Biol. Chem. 276:522–28 [Google Scholar]
  45. Watson SP, Hambleton S. 45.  1989. Phosphorylation-dependent and -independent pathways of platelet aggregation. Biochem. J. 258:479–85 [Google Scholar]
  46. Tabuchi A, Yoshioka A, Higashi T, Shirakawa R, Nishioka H. 46.  et al. 2003. Direct demonstration of involvement of protein kinase Cα in the Ca2+-induced platelet aggregation. J. Biol. Chem. 278:26374–79 [Google Scholar]
  47. Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B. 47.  et al. 2006. Reconstructing and deconstructing agonist-induced activation of integrin αIIbβ3. Curr. Biol. 16:1796–806 [Google Scholar]
  48. Konopatskaya O, Gilio K, Harper MT, Zhao Y, Cosemans JMEM. 48.  et al. 2009. PKCα regulates platelet granule secretion and thrombus formation in mice. J. Clin. Investig. 119:399–407 [Google Scholar]
  49. Buensuceso CS, Obergfell A, Soriani A, Eto K, Kiosses WB. 49.  et al. 2005. Regulation of outside-in signaling in platelets by integrin-associated protein kinase Cβ. J. Biol. Chem. 280:644–53 [Google Scholar]
  50. Gilio K, Harper MT, Cosemans JMEM, Konopatskaya O, Munnix ICA. 50.  et al. 2010. Functional divergence of platelet protein kinase C (PKC) isoforms in thrombus formation on collagen. J. Biol. Chem. 285:23410–19 [Google Scholar]
  51. Soriani A, Moran B, De Virgilio M, Kawakami T, Altman A. 51.  et al. 2006. A role for PKCθ in outside-in αIIbβ3 signaling. J. Thromb. Haemost. 4:648–55 [Google Scholar]
  52. Cohen S, Braiman A, Shubinsky G, Ohayon A, Altman A, Isakov N. 52.  2009. PKCθ is required for hemostasis and positive regulation of thrombin-induced platelet aggregation and α-granule secretion. Biochem. Biophys. Res. Commun. 385:22–27 [Google Scholar]
  53. Nagy B Jr, Bhavaraju K, Getz T, Bynagari YS, Kim S, Kunapuli SP. 53.  2009. Impaired activation of platelets lacking protein kinase C-θ isoform. Blood 113:2557–67 [Google Scholar]
  54. Doulatov S, Notta F, Eppert K, Nguyen LT, Ohashi PS, Dick JE. 54.  2010. Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nat. Immunol. 11:585–93 [Google Scholar]
  55. Baxter GT, Miller DL, Kuo RC, Wada HG, Owicki JC. 55.  1992. PKCε is involved in granulocyte-macrophage colony-stimulating factor signal transduction: evidence from microphysiometry and antisense oligonucleotide experiments. Biochemistry 31:10950–54 [Google Scholar]
  56. Kanayasu-Toyoda T, Suzuki T, Oshizawa T, Uchida E, Hayakawa T, Yamaguchi T. 56.  2007. Granulocyte colony-stimulating factor promotes the translocation of protein kinase Cι in neutrophilic differentiation cells. J. Cell Physiol. 211:189–96 [Google Scholar]
  57. Sergeant S, McPhail LC. 57.  1997. Opsonized zymosan stimulates the redistribution of protein kinase C isoforms in human neutrophils. J. Immunol. 159:2877–85 [Google Scholar]
  58. Dekker LV, Leitges M, Altschuler G, Mistry N, McDermott A. 58.  et al. 2000. Protein kinase C-β contributes to NADPH oxidase activation in neutrophils. Biochem. J. 347:Pt. 1285–89 [Google Scholar]
  59. Bertram A, Ley K. 59.  2011. Protein kinase C isoforms in neutrophil adhesion and activation. Arch. Immunol. Ther. Exp. 59:79–87 [Google Scholar]
  60. Fontayne A, Dang PM, Gougerot-Pocidalo MA, El-Benna J. 60.  2002. Phosphorylation of p47phox sites by PKC α, βII, δ, and ζ: effect on binding to p22phox and on NADPH oxidase activation. Biochemistry 41:7743–50 [Google Scholar]
  61. Chou WH, Choi DS, Zhang H, Mu D, McMahon T. 61.  et al. 2004. Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury. J. Clin. Investig. 114:49–56 [Google Scholar]
  62. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y. 62.  et al. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–35 [Google Scholar]
  63. Miura K, MacGlashan DW Jr. 63.  1998. Expression of protein kinase C isozymes in human basophils: regulation by physiological and nonphysiological stimuli. Blood 92:1206–18 [Google Scholar]
  64. Kato M, Yamaguchi T, Tachibana A, Suzuki M, Izumi T. 64.  et al. 2005. An atypical protein kinase C, PKCζ, regulates human eosinophil effector functions. Immunology 116:193–202 [Google Scholar]
  65. Kitaura J, Eto K, Kinoshita T, Kawakami Y, Leitges M. 65.  et al. 2005. Regulation of highly cytokinergic IgE-induced mast cell adhesion by Src, Syk, Tec, and protein kinase C family kinases. J. Immunol. 174:4495–504 [Google Scholar]
  66. Kawakami Y, Kitaura J, Hartman SE, Lowell CA, Siraganian RP, Kawakami T. 66.  2000. Regulation of protein kinase CβI by two protein-tyrosine kinases, Btk and Syk. PNAS 97:7423–28 [Google Scholar]
  67. Kawakami Y, Kitaura J, Yao L, McHenry RW, Kawakami Y. 67.  et al. 2003. A Ras activation pathway dependent on Syk phosphorylation of protein kinase C. PNAS 100:9470–75 [Google Scholar]
  68. Nechushtan H, Leitges M, Cohen C, Kay G, Razin E. 68.  2000. Inhibition of degranulation and interleukin-6 production in mast cells derived from mice deficient in protein kinase Cβ. Blood 95:1752–57 [Google Scholar]
  69. Leitges M, Gimborn K, Elis W, Kalesnikoff J, Hughes MR. 69.  et al. 2002. Protein kinase C-δ is a negative regulator of antigen-induced mast cell degranulation. Mol. Cell. Biol. 22:3970–80 [Google Scholar]
  70. Whetton AD, Heyworth CM, Nicholls SE, Evans CA, Lord JM. 70.  et al. 1994. Cytokine-mediated protein kinase C activation is a signal for lineage determination in bipotential granulocyte macrophage colony-forming cells. J. Cell Biol. 125:651–59 [Google Scholar]
  71. Pierce A, Heyworth CM, Nicholls SE, Spooncer E, Dexter TM. 71.  et al. 1998. An activated protein kinase C α gives a differentiation signal for hematopoietic progenitor cells and mimicks macrophage colony-stimulating factor-stimulated signaling events. J. Cell Biol. 140:1511–18 [Google Scholar]
  72. Hamdorf M, Berger A, Schüle S, Reinhardt J, Flory E. 72.  2011. PKCδ-induced PU.1 phosphorylation promotes hematopoietic stem cell differentiation to dendritic cells. Stem Cells 29:297–306 [Google Scholar]
  73. Castrillo A, Pennington DJ, Otto F, Parker PJ, Owen MJ, Bosca L. 73.  2001. Protein kinase Cε is required for macrophage activation and defense against bacterial infection. J. Exp. Med. 194:1231–42 [Google Scholar]
  74. Langlet C, Springael C, Johnson J, Thomas S, Flamand V. 74.  et al. 2010. PKC-α controls MYD88-dependent TLR/IL-1R signaling and cytokine production in mouse and human dendritic cells. Eur. J. Immunol. 40:505–15 [Google Scholar]
  75. Strasser D, Neumann K, Bergmann H, Marakalala MJ, Guler R. 75.  et al. 2012. Syk kinase–coupled C-type lectin receptors engage protein kinase C-δ to elicit Card9 adaptor–mediated innate immunity. Immunity 36:32–42 [Google Scholar]
  76. Schwegmann A, Guler R, Cutler AJ, Arendse B, Horsnell WG. 76.  et al. 2007. Protein kinase C δ is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes. PNAS 104:16251–56 [Google Scholar]
  77. Chen L, Haider K, Ponda M, Cariappa A, Rowitch D, Pillai S. 77.  2001. Protein kinase C–associated kinase (PKK), a novel membrane-associated, ankyrin repeat–containing protein kinase. J. Biol. Chem. 276:21737–44 [Google Scholar]
  78. Cariappa A, Chen L, Haider K, Tang M, Nebelitskiy E. 78.  et al. 2003. A catalytically inactive form of protein kinase C–associated kinase/receptor interacting protein 4, a protein kinase C β–associated kinase that mediates NF-κB activation, interferes with early B cell development. J. Immunol. 171:1875–80 [Google Scholar]
  79. Su TT, Guo B, Kawakami Y, Sommer K, Chae K. 79.  et al. 2002. PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling. Nat. Immunol. 3:780–86 [Google Scholar]
  80. Saijo K, Mecklenbrauker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A. 80.  2002. Protein kinase C β controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase α. J. Exp. Med. 195:1647–52 [Google Scholar]
  81. Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S. 81.  et al. 1996. Immunodeficiency in protein kinase Cβ–deficient mice. Science 273:788–91 [Google Scholar]
  82. Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y. 82.  et al. 2002. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416:865–69 [Google Scholar]
  83. Mecklenbrauker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A. 83.  2002. Protein kinase Cδ controls self-antigen–induced B-cell tolerance. Nature 416:860–65 [Google Scholar]
  84. Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W. 84.  et al. 2013. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood 121:3112–16 [Google Scholar]
  85. Limnander A, Depeille P, Freedman TS, Liou J, Leitges M. 85.  et al. 2011. STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nat. Immunol. 12:425–33 [Google Scholar]
  86. Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP. 86.  2014. Protein kinase Cδ promotes transitional B cell–negative selection and limits proximal B cell receptor signaling to enforce tolerance. Mol. Cell. Biol. 34:1474–85 [Google Scholar]
  87. Zhang EY, Kong KF, Altman A. 87.  2013. The Yin and Yang of protein kinase C-θ (PKCθ): a novel drug target for selective immunosuppression. Adv. Pharmacol. 66:267–312 [Google Scholar]
  88. Kong KF, Altman A. 88.  2013. In and out of the bull's eye: protein kinase Cs in the immunological synapse. Trends Immunol. 34:234–42 [Google Scholar]
  89. De Obaldia ME, Bhandoola A. 89.  2015. Transcriptional regulation of innate and adaptive lymphocyte lineages. Annu. Rev. Immunol. 33:607–42 [Google Scholar]
  90. Yui MA, Rothenberg EV. 90.  2014. Developmental gene networks: a triathlon on the course to T cell identity. Nat. Rev. Immunol. 14:529–45 [Google Scholar]
  91. Tremmel DM, Resad S, Little CJ, Wesley CS. 91.  2013. Notch and PKC are involved in formation of the lateral region of the dorso-ventral axis in Drosophila embryos. PLOS ONE 8:e67789 [Google Scholar]
  92. Noonan DJ, Isakov N, Theofilopoulos AN, Dixon FJ, Altman A. 92.  1987. Protein kinase C–activating phorbol esters augment expression of T cell receptor genes. Eur. J. Immunol. 17:803–7 [Google Scholar]
  93. Lindsten T, June CH, Thompson CB. 93.  1988. Transcription of T cell antigen receptor genes is induced by protein kinase C activation. J. Immunol. 141:1769–74 [Google Scholar]
  94. Michie AM, Soh JW, Hawley RG, Weinstein IB, Zuniga-Pflucker JC. 94.  2001. Allelic exclusion and differentiation by protein kinase C–mediated signals in immature thymocytes. PNAS 98:609–14 [Google Scholar]
  95. Mick VE, Starr TK, McCaughtry TM, McNeil LK, Hogquist KA. 95.  2004. The regulated expression of a diverse set of genes during thymocyte positive selection in vivo. J. Immunol. 173:5434–44 [Google Scholar]
  96. Niederberger N, Buehler LK, Ampudia J, Gascoigne NR. 96.  2005. Thymocyte stimulation by anti-TCR-β, but not by anti-TCR-α, leads to induction of developmental transcription program. J. Leukoc. Biol. 77:830–41 [Google Scholar]
  97. Morley SC, Weber KS, Kao H, Allen PM. 97.  2008. Protein kinase C-θ is required for efficient positive selection. J. Immunol. 181:4696–708 [Google Scholar]
  98. Fu G, Hu J, Niederberger-Magnenat N, Rybakin V, Casas J. 98.  et al. 2011. Protein kinase C η is required for T cell activation and homeostatic proliferation. Sci. Signal. 4:ra84 [Google Scholar]
  99. Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. 99.  1998. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82–86 [Google Scholar]
  100. Monks CR, Kupfer H, Tamir I, Barlow A, Kupfer A. 100.  1997. Selective modulation of protein kinase C-θ during T-cell activation. Nature 385:83–86 [Google Scholar]
  101. Dustin ML. 101.  2012. Signaling at neuro/immune synapses. J. Clin. Investig. 122:1149–55 [Google Scholar]
  102. Krummel MF, Sjaastad MD, Wulfing C, Davis MM. 102.  2000. Differential clustering of CD4 and CD3ζ during T cell recognition. Science 289:1349–52 [Google Scholar]
  103. Bunnell SC, Kapoor V, Trible RP, Zhang W, Samelson LE. 103.  2001. Dynamic actin polymerization drives T cell receptor–induced spreading: a role for the signal transduction adaptor LAT. Immunity 14:315–29 [Google Scholar]
  104. Varma R, Campi G, Yokosuka T, Saito T, Dustin ML. 104.  2006. T cell receptor–proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25:117–27 [Google Scholar]
  105. Vardhana S, Choudhuri K, Varma R, Dustin ML. 105.  2010. Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster. Immunity 32:531–40 [Google Scholar]
  106. Yokosuka T, Kobayashi W, Sakata-Sogawa K, Takamatsu M, Hashimoto-Tane A. 106.  et al. 2008. Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters and protein kinase C θ translocation. Immunity 29:589–601 [Google Scholar]
  107. Quann EJ, Liu X, Altan-Bonnet G, Huse M. 107.  2011. A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells. Nat. Immunol. 12:647–54 [Google Scholar]
  108. Bi K, Tanaka Y, Coudronniere N, Sugie K, Hong S. 108.  et al. 2001. Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation. Nat. Immunol. 2:556–63 [Google Scholar]
  109. Spitaler M, Emslie E, Wood CD, Cantrell D. 109.  2006. Diacylglycerol and protein kinase D localization during T lymphocyte activation. Immunity 24:535–46 [Google Scholar]
  110. Kong KF, Yokosuka T, Canonigo-Balancio AJ, Isakov N, Saito T, Altman A. 110.  2011. 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. Nat. Immunol. 12:1105–12 [Google Scholar]
  111. Basu R, Chen Y, Quann EJ, Huse M. 111.  2014. The variable hinge region of novel PKCs determines localization to distinct regions of the immunological synapse. PLOS ONE 9:e95531 [Google Scholar]
  112. Potter TA, Grebe K, Freiberg B, Kupfer A. 112.  2001. Formation of supramolecular activation clusters on fresh ex vivo CD8+ T cells after engagement of the T cell antigen receptor and CD8 by antigen-presenting cells. PNAS 98:12624–29 [Google Scholar]
  113. Stinchcombe JC, Bossi G, Booth S, Griffiths GM. 113.  2001. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15:751–61 [Google Scholar]
  114. Ma JS, Haydar TF, Radoja S. 114.  2008. Protein kinase C δ localizes to secretory lysosomes in CD8+ CTL and directly mediates TCR signals leading to granule exocytosis–mediated cytotoxicity. J. Immunol. 181:4716–22 [Google Scholar]
  115. Grybko MJ, Pores-Fernando AT, Wurth GA, Zweifach A. 115.  2007. Protein kinase C activity is required for cytotoxic T cell lytic granule exocytosis, but the θ isoform does not play a preferential role. J. Leukoc. Biol. 81:509–19 [Google Scholar]
  116. Liu Y, Witte S, Liu YC, Doyle M, Elly C, Altman A. 116.  2000. Regulation of protein kinase Cθ function during T cell activation by Lck-mediated tyrosine phosphorylation. J. Biol. Chem. 275:3603–9 [Google Scholar]
  117. Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM. 117.  et al. 2011. The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells. Nat. Immunol. 12:1113–18 [Google Scholar]
  118. Liu Y, Graham C, Li A, Fisher RJ, Shaw S. 118.  2002. 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. Biochem. J. 361:255–65 [Google Scholar]
  119. Cartwright NG, Kashyap AK, Schaefer BC. 119.  2011. An active kinase domain is required for retention of PKCθ at the T cell immunological synapse. Mol. Biol. Cell 22:3491–97 [Google Scholar]
  120. Thuille N, Heit I, Fresser F, Krumbock N, Bauer B. 120.  et al. 2005. Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCθ in T lymphocytes. EMBO J. 24:3869–80 [Google Scholar]
  121. Diaz-Flores E, Siliceo M, Martinez AC, Merida I. 121.  2003. Membrane translocation of protein kinase Cθ during T lymphocyte activation requires phospholipase C-γ–generated diacylglycerol. J. Biol. Chem. 278:29208–15 [Google Scholar]
  122. Matsumoto R, Wang D, Blonska M, Li H, Kobayashi M. 122.  et al. 2005. Phosphorylation of CARMA1 plays a critical role in T Cell receptor–mediated NF-κB activation. Immunity 23:575–85 [Google Scholar]
  123. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ. 123.  et al. 2000. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404:402–7 [Google Scholar]
  124. Pfeifhofer C, Kofler K, Gruber T, Tabrizi NG, Lutz C. 124.  et al. 2003. Protein kinase C θ affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells. J. Exp. Med. 197:1525–35 [Google Scholar]
  125. Benes CH, Wu N, Elia AE, Dharia T, Cantley LC, Soltoff SP. 125.  2005. The C2 domain of PKCδ is a phosphotyrosine binding domain. Cell 121:271–80 [Google Scholar]
  126. Stahelin RV, Kong KF, Raha S, Tian W, Melowic HR. 126.  et al. 2012. Protein kinase Cθ C2 domain is a phosphotyrosine binding module that plays a key role in its activation. J. Biol. Chem. 287:30518–28 [Google Scholar]
  127. Altman A, Kaminski S, Busuttil V, Droin N, Hu J. 127.  et al. 2004. Positive feedback regulation of PLCγ1/Ca2+ signaling by PKCθ in restimulated T cells via a Tec kinase–dependent pathway. Eur. J. Immunol. 34:2001–11 [Google Scholar]
  128. Manicassamy S, Sadim M, Ye RD, Sun Z. 128.  2006. Differential roles of PKC-θ in the regulation of intracellular calcium concentration in primary T cells. J. Mol. Biol. 355:347–59 [Google Scholar]
  129. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. 129.  1986. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136:2348–57 [Google Scholar]
  130. Glimcher LH, Murphy KM. 130.  2000. Lineage commitment in the immune system: The T helper lymphocyte grows up. Genes Dev 14:1693–711 [Google Scholar]
  131. Marsland BJ, Soos TJ, Spath G, Littman DR, Kopf M. 131.  2004. Protein kinase C θ is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. J. Exp. Med. 200:181–89 [Google Scholar]
  132. Salek-Ardakani S, So T, Halteman BS, Altman A, Croft M. 132.  2004. Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase C θ. J. Immunol. 173:6440–47 [Google Scholar]
  133. Salek-Ardakani S, So T, Halteman BS, Altman A, Croft M. 133.  2005. Protein kinase Cθ controls Th1 cells in experimental autoimmune encephalomyelitis. J. Immunol. 175:7635–41 [Google Scholar]
  134. Tan SL, Zhao J, Bi C, Chen XC, Hepburn DL. 134.  et al. 2006. Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase C θ–deficient mice. J. Immunol. 176:2872–79 [Google Scholar]
  135. Giannoni F, Lyon AB, Wareing MD, Dias PB, Sarawar SR. 135.  2005. Protein kinase C θ is not essential for T-cell–mediated clearance of murine γ herpesvirus 68. J. Virol. 79:6808–13 [Google Scholar]
  136. Marsland BJ, Nembrini C, Schmitz N, Abel B, Krautwald S. 136.  et al. 2005. Innate signals compensate for the absence of PKC-θ during in vivo CD8+ T cell effector and memory responses. PNAS 102:14374–79 [Google Scholar]
  137. Valenzuela JO, Iclozan C, Hossain MS, Prlic M, Hopewell E. 137.  et al. 2009. PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice. J. Clin. Investig. 119:3774–86 [Google Scholar]
  138. Zanin-Zhorov A, Dustin ML, Blazar BR. 138.  2011. PKC-θ function at the immunological synapse: prospects for therapeutic targeting. Trends Immunol. 32:358–63 [Google Scholar]
  139. von Essen M, Nielsen MW, Bonefeld CM, Boding L, Larsen JM. 139.  et al. 2006. Protein kinase C (PKC) α and PKC θ are the major PKC isotypes involved in TCR down-regulation. J. Immunol. 176:7502–10 [Google Scholar]
  140. Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R. 140.  et al. 2009. PKC-θ modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Sci. Signal. 2:ra30 [Google Scholar]
  141. Haarberg KM, Li J, Heinrichs J, Wang D, Liu C. 141.  et al. 2013. Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice. Blood 122:2500–11 [Google Scholar]
  142. Skvara H, Dawid M, Kleyn E, Wolff B, Meingassner JG. 142.  et al. 2008. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J. Clin. Investig. 118:3151–59 [Google Scholar]
  143. Barouch-Bentov R, Lemmens EE, Hu J, Janssen EM, Droin NM. 143.  et al. 2005. Protein kinase C-θ is an early survival factor required for differentiation of effector CD8+ T cells. J. Immunol. 175:5126–34 [Google Scholar]
  144. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM. 144.  et al. 2007. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315:1687–91 [Google Scholar]
  145. Metz PJ, Arsenio J, Kakaradov B, Kim SH, Remedios KA. 145.  et al. 2015. Regulation of asymmetric division and CD8+ T lymphocyte fate specification by protein kinase Cζ and protein kinase Cλ/ι. J. Immunol. 194:2249–59 [Google Scholar]
  146. Josefowicz SZ, Lu LF, Rudensky AY. 146.  2012. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30:531–64 [Google Scholar]
  147. Morikawa H, Sakaguchi S. 147.  2014. Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunol. Rev. 259:192–205 [Google Scholar]
  148. Zanin-Zhorov A, Ding Y, Kumari S, Attur M, Hippen KL. 148.  et al. 2010. Protein kinase C-θ mediates negative feedback on regulatory T cell function. Science 328:372–76 [Google Scholar]
  149. Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H. 149.  et al. 2010. Spatiotemporal basis of CTLA-4 costimulatory molecule–mediated negative regulation of T cell activation. Immunity 33:326–39 [Google Scholar]
  150. Chuck MI, Zhu M, Shen S, Zhang W. 150.  2010. The role of the LAT–PLC-γ1 interaction in T regulatory cell function. J. Immunol. 184:2476–86 [Google Scholar]
  151. Wing K, Yamaguchi T, Sakaguchi S. 151.  2011. Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol. 32:428–33 [Google Scholar]
  152. Kong KF, Fu G, Zhang Y, Yokosuka T, Casas J. 152.  et al. 2014. Protein kinase C-η controls CTLA-4–mediated regulatory T cell function. Nat. Immunol. 15:465–72 [Google Scholar]
  153. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC. 153.  et al. 2011. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell–mediated inflammation. Immunity 34:566–78 [Google Scholar]
  154. Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ. 154.  et al. 2011. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10–dependent manner. Immunity 34:554–65 [Google Scholar]
  155. Sun JC, Lanier LL. 155.  2011. NK cell development, homeostasis and function: parallels with CD8+ T cells. Nat. Rev. Immunol. 11:645–57 [Google Scholar]
  156. Chow SC, Ng J, Nordstedt C, Fredholm BB, Jondal M. 156.  1988. Phosphoinositide breakdown and evidence for protein kinase C involvement during human NK killing. Cell Immunol. 114:96–103 [Google Scholar]
  157. Ting AT, Schoon RA, Abraham RT, Leibson PJ. 157.  1992. Interaction between protein kinase C–dependent and G protein–dependent pathways in the regulation of natural killer cell granule exocytosis. J. Biol. Chem. 267:23957–62 [Google Scholar]
  158. Chuang SS, Lee JK, Mathew PA. 158.  2003. Protein kinase C is involved in 2B4 (CD244)-mediated cytotoxicity and AP-1 activation in natural killer cells. Immunology 109:432–39 [Google Scholar]
  159. Tassi I, Cella M, Presti R, Colucci A, Gilfillan S. 159.  et al. 2008. NK cell–activating receptors require PKC-θ for sustained signaling, transcriptional activation, and IFN-γ secretion. Blood 112:4109–16 [Google Scholar]
  160. Aguilo JI, Garaude J, Pardo J, Villalba M, Anel A. 160.  2009. Protein kinase C-θ is required for NK cell activation and in vivo control of tumor progression. J. Immunol. 182:1972–81 [Google Scholar]
  161. Nabekura T, Kanaya M, Shibuya A, Fu G, Gascoigne NR, Lanier LL. 161.  2014. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40:225–34 [Google Scholar]
  162. Vitale M, Bassini A, Secchiero P, Mirandola P, Ponti C. 162.  et al. 2002. NK-active cytokines IL-2, IL-12, and IL-15 selectively modulate specific protein kinase C (PKC) isoforms in primary human NK cells. Anat. Rec. 266:87–92 [Google Scholar]
  163. Comet NR, Aguilo JI, Rathore MG, Catalan E, Garaude J. 163.  et al. 2014. IFNα signaling through PKC-θ is essential for antitumor NK cell function. Oncoimmunology 3:e948705 [Google Scholar]
  164. Fang X, Wang R, Ma J, Ding Y, Shang W, Sun Z. 164.  2012. Ameliorated ConA-induced hepatitis in the absence of PKC-θ. PLOS ONE 7:e31174 [Google Scholar]
  165. Sutcliffe EL, Bunting KL, He YQ, Li J, Phetsouphanh C. 165.  et al. 2011. Chromatin-associated protein kinase C-θ regulates an inducible gene expression program and microRNAs in human T lymphocytes. Mol. Cell 41:704–19 [Google Scholar]
  166. Friedman E, Isaksson P, Rafter J, Marian B, Winawer S, Newmark H. 166.  1989. Fecal diglycerides as selective endogenous mitogens for premalignant and malignant human colonic epithelial cells. Cancer Res. 49:544–48 [Google Scholar]
  167. Morotomi M, Guillem JG, LoGerfo P, Weinstein IB. 167.  1990. Production of diacylglycerol, an activator of protein kinase C, by human intestinal microflora. Cancer Res. 50:3595–99 [Google Scholar]
  168. Vulevic J, McCartney AL, Gee JM, Johnson IT, Gibson GR. 168.  2004. Microbial species involved in production of 1,2-sn-diacylglycerol and effects of phosphatidylcholine on human fecal microbiota. Appl. Environ. Microbiol. 70:5659–66 [Google Scholar]
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