Abstract
Protein kinase C molecules regulate both positive and negative signal transduction pathways essential for the initiation and homeostasis of immune responses. There are multiple isoforms of protein kinase C that are activated differently by calcium and diacylglycerol, and these are activated mainly by antigen receptors in T cells, B cells and mast cells. Additionally, mammals express several other diacylglycerol binding proteins that are linked to a network of key signal transduction pathways that control lymphocyte biology. Diacylglycerol and protein kinase C regulate a broad range of gene transcription programs but also modulate integrins, chemokine responses and antigen receptors, thereby regulating lymphocyte adhesion, migration, differentiation and proliferation.
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References
Mellor, H. & Parker, P.J. The extended protein kinase C superfamily. Biochem. J. 332, 281–292 (1998).
Nishizuka, Y. Discovery and prospect of protein kinase C research: epilogue. J. Biochem. (Tokyo) 133, 155–158 (2003).
Weiss, A., Irving, B.A., Tan, L.K. & Koretzky, G.A. Signal transduction by the T cell antigen receptor. Semin. Immunol. 3, 313–324 (1991).
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. J. Biol. Chem. 270, 9833–9839 (1995).
Hogg, N., Laschinger, M., Giles, K. & McDowall, A. T-cell integrins: more than just sticking points. J. Cell. Sci. 116, 4695–4705 (2003).
Ivaska, J. et al. Integrin-protein kinase C relationships. Biochem. Soc. Trans. 31, 90–93 (2003).
Weiss, A., Wiskocil, R.L. & Stobo, J.D. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL-2 production reflects events occurring at a pre-translational level. J. Immunol. 133, 123–128 (1984).
Isakov, N., Mally, M.I., Scholz, W. & Altman, A. T-lymphocyte activation: the role of protein kinase C and the bifurcating inositol phospholipid signal transduction pathway. Immunol. Rev. 95, 89–111 (1987).
Xing, T., Higgins, V.J. & Blumwald, E. Regulation of plant defense response to fungal pathogens: two types of protein kinases in the reversible phosphorylation of the host plasma membrane H+-ATPase. Plant. Cell 8, 555–564 (1996).
Meyerowitz, E.M. Plants compared to animals: the broadest comparative study of development. Science 295, 1482–1485 (2002).
Pettitt, T.R. et al. Diacylglycerol and phosphatidate generated by phospholipases C and D, respectively, have distinct fatty acid compositions and functions. Phospholipase D-derived diacylglycerol does not activate protein kinase C in porcine aortic endothelial cells. J. Biol. Chem. 272, 17354–17359 (1997).
Sanjuan, M.A. et al. T cell activation in vivo targets diacylglycerol kinase α to the membrane: a novel mechanism for Ras attenuation. J. Immunol. 170, 2877–2883 (2003).
Zhong, X.P. et al. Enhanced T cell responses due to diacylglycerol kinase ζ deficiency. Nat. Immunol. 4, 882–890 (2003).
Tan, S.L. & Parker, P.J. Emerging and diverse roles of protein kinase C in immune cell signalling. Biochem. J. 376, 545–552 (2003).
Geiger, M. et al. Defining the human targets of phorbol ester and diacylglycerol. Curr. Opin. Mol. Ther. 5, 631–641 (2003).
Kazanietz, M.G. Novel “nonkinase” phorbol ester receptors: the C1 domain connection. Mol. Pharmacol. 61, 759–767 (2002).
Ebinu, J.O. et al. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998).
Rykx, A. et al. Protein kinase D: a family affair. FEBS Lett. 546, 81–86 (2003).
Tan, I., Seow, K.T., Lim, L. & Leung, T. Intermolecular and intramolecular interactions regulate catalytic activity of myotonic dystrophy kinase-related Cdc42-binding kinase α. Mol. Cell. Biol. 21, 2767–2778 (2001).
Waldron, R.T. & Rozengurt, E. Protein kinase C phosphorylates protein kinase D activation loop Ser744 and Ser748 and releases autoinhibition by the pleckstrin homology domain. J. Biol. Chem. 278, 154–163 (2003).
Izquierdo, M., Downward, J., Graves, J.D. & Cantrell, D.A. Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells. Mol. Cell. Biol. 12, 3305–3312 (1992).
Teixeira, C., Stang, S.L., Zheng, Y., Beswick, N.S. & Stone, J.C. Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3. Blood 102, 1414–1420 (2003).
Luo, B., Prescott, S.M. & Topham, M.K. Protein kinase C α phosphorylates and negatively regulates diacylglycerol kinase ζ. J. Biol. Chem. 278, 39542–39547 (2003).
Luo, B., Prescott, S.M. & Topham, M.K. Association of diacylglycerol kinase ζ with protein kinase C α: spatial regulation of diacylglycerol signaling. J. Cell Biol. 160, 929–937 (2003).
Newton, A.C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem. J. 370, 361–371 (2003).
Newton, A.C. Protein kinase C: structure, function, and regulation. J. Biol. Chem. 270, 28495–28498 (1995).
Monks, C.R., Freiberg, B.A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).
Arendt, C.W., Albrecht, B., Soos, T.J. & Littman, D.R. Protein kinase C-θ: signaling from the center of the T-cell synapse. Curr. Opin. Immunol. 14, 323–330 (2002).
Diaz-Flores, E., Siliceo, M., Martinez, A.C. & Merida, I. Membrane translocation of protein kinase Cθ during T lymphocyte activation requires phospholipase C-γ-generated diacylglycerol. J. Biol. Chem. 278, 29208–29215 (2003).
Altman, A. & Villalba, M. Protein kinase C-θ (PKC-θ): it's all about location, location, location. Immunol. Rev. 192, 53–63 (2003).
Baier, G. The PKC gene module: molecular biosystematics to resolve its T cell functions. Immunol. Rev. 192, 64–79 (2003).
Acuto, O. & Cantrell, D. T cell activation and the cytoskeleton. Annu. Rev. Immunol. 18, 165–184 (2000).
Koretzky, G.A. & Myung, P.S. Positive and negative regulation of T-cell activation by adaptor proteins. Nat. Rev. Immunol. 1, 95–107 (2001).
Ward, S.G. & Cantrell, D.A. Phosphoinositide 3-kinases in T lymphocyte activation. Curr. Opin. Immunol. 13, 332–338 (2001).
Vanhaesebroeck, B. & Alessi, D.R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561–576 (2000).
Collins, B.J., Deak, M., Arthur, J.S., Armit, L.J. & Alessi, D.R. In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J. 22, 4202–4211 (2003).
Birchall, A.M. et al. Ro 32-0432, a selective and orally active inhibitor of protein kinase C prevents T-cell activation. J. Pharmacol. Exp. Ther. 268, 922–929 (1994).
Bit, R.A. et al. Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction. J. Med. Chem. 36, 21–29 (1993).
Davies, S.P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95–105 (2000).
Morgan, M.M. et al. Superantigen-induced T cell:B cell conjugation is mediated by LFA-1 and requires signaling through Lck, but not ZAP-70. J. Immunol. 167, 5708–5718 (2001).
Sasahara, Y. et al. Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Mol. Cell 10, 1269–1281 (2002).
McLeod, S.J. & Gold, M.R. Activation and function of the Rap1 GTPase in B lymphocytes. Int. Rev. Immunol. 20, 763–789 (2001).
Bos, J.L., de Rooij, J. & Reedquist, K.A. Rap1 signalling: adhering to new models. Nat. Rev. Mol. Cell. Biol. 2, 369–377 (2001).
Sebzda, E., Bracke, M., Tugal, T., Hogg, N. & Cantrell, D.A. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nat. Immunol. 3, 251–258 (2002).
Liu, L. et al. The GTPase Rap1 regulates phorbol 12-myristate 13-acetate-stimulated but not ligand-induced β1 integrin-dependent leukocyte adhesion. J. Biol. Chem. 277, 40893–40900 (2002).
Sotsios, Y., Blair, P.J., Westwick, J. & Ward, S.G. Disparate effects of phorbol esters, CD3 and the costimulatory receptors CD2 and CD28 on RANTES secretion by human T lymphocytes. Immunology 101, 30–37 (2000).
Guinamard, R. et al. B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1α chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4. J. Exp. Med. 189, 1461–1466 (1999).
Dustin, M.L. Regulation of T cell migration through formation of immunological synapses: the stop signal hypothesis. Adv. Exp. Med. Biol. 512, 191–201 (2002).
Mecklenbrauker, I., Saijo, K., Zheng, N.Y., Leitges, M. & Tarakhovsky, A. Protein kinase Cδ controls self-antigen-induced B-cell tolerance. Nature 416, 860–865 (2002).
Miyamoto, A. et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416, 865–869 (2002).
Leitges, M. et al. Protein kinase C-delta is a negative regulator of antigen-induced mast cell degranulation. Mol. Cell. Biol. 22, 3970–3980 (2002).
Cantrell, D.A., Davies, A.A. & Crumpton, M.J. Activators of protein kinase C down-regulate and phosphorylate the T3/T-cell antigen receptor complex of human T lymphocytes. Proc. Natl. Acad. Sci. USA 82, 8158–8162 (1985).
Minami, Y., Samelson, L.E. & Klausner, R.D. Internalization and cycling of the T cell antigen receptor. Role of protein kinase C. J. Biol. Chem. 262, 13342–13347 (1987).
Bonefeld, C.M. et al. TCR comodulation of nonengaged TCR takes place by a protein kinase C and CD3 γ di-leucine-based motif-dependent mechanism. J. Immunol. 171, 3003–3009 (2003).
Williams, D.H., Woodrow, M., Cantrell, D.A. & Murray, E.J. Protein kinase C is not a downstream effector of p21ras in activated T cells. Eur. J. Immunol. 25, 42–47 (1995).
Leitges, M. et al. Immunodeficiency in protein kinase Cβ-deficient mice. Science 273, 788–791 (1996).
Saijo, K. et al. Protein kinase C β controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase α. J. Exp. Med. 195, 1647–1652 (2002).
Martin, P. et al. Role of ζ PKC in B-cell signaling and function. EMBO J. 21, 4049–4057 (2002).
Saijo, K. et al. Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development. Nat. Immunol. 4, 274–279 (2003).
Baier, G. et al. 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 (1993).
Pfeifhofer, C. et al. Protein kinase C θ affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells. J. Exp. Med. 197, 1525–1535 (2003).
Sun, Z. et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000).
Berg-Brown, N.N. et al. PKC-θ signals activation versus tolerance in vivo. J. Exp. Med. 199, 743–752 (2004).
Cheng, A.M. et al. The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling. Proc. Natl. Acad. Sci. USA 94, 9797–9801 (1997).
Zhang, W. et al. Essential role of LAT in T cell development. Immunity 10, 323–332 (1999).
Clements, J.L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281, 416–419 (1998).
Gomez, M., Tybulewicz, V. & Cantrell, D.A. Control of pre-T cell proliferation and differentiation by the GTPase Rac-I. Nat. Immunol. 1, 348–352 (2000).
Voll, R.E. et al. NF-κB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13, 677–689 (2000).
Hinton, H., Alessi, D.R. & Cantrell, D. The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nat. Immunol. 5, 539–545 (2004).
Matthews, S., Iglesias, T., Cantrell, D. & Rozengurt, E. Dynamic re-distribution of protein kinase D (PKD) as revealed by a GFP-PKD fusion protein: dissociation from PKD activation. FEBS Lett. 457, 515–521 (1999).
Matthews, S.A., Rozengurt, E. & Cantrell, D. Protein kinase D. A selective target for antigen receptors and a downstream target for protein kinase C in lymphocytes. J. Exp. Med. 191, 2075–2082 (2000).
Matthews, S.A., Iglesias, T., Rozengurt, E. & Cantrell, D. Spatial and temporal regulation of protein kinase D (PKD). EMBO J. 19, 2935–2945 (2000).
Marklund, U., Lightfoot, K. & Cantrell, D. Intracellular location and cell context-dependent function of protein kinase D. Immunity 19, 491–501 (2003).
Michie, A. & Zuniga-Pflucker, J. Regulation of thymocyte differentiation: pre-TCR signals and β-selection. Semin. Immunol. 14, 311 (2002).
Michie, A.M., Soh, J.W., Hawley, R.G., Weinstein, I.B. & Zuniga-Pflucker, J.C. Allelic exclusion and differentiation by protein kinase C-mediated signals in immature thymocytes. Proc. Natl. Acad. Sci. USA 98, 609–614 (2001).
Li, Y. et al. SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway. EMBO J. (2004).
Astoul, E. et al. Approaches to define antigen receptor-induced serine kinase signal transduction pathways. J. Biol. Chem. 278, 9267–9275 (2003).
Acknowledgements
We thank A. Altman, G. Baier and D. Littman and current and past members of the Lymphocyte Activation Laboratory for discussions. Supported by European Union Marie Curie (MCFI-2001-01855 to M.S.) and Wellcome Trust (D.C.).
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Spitaler, M., Cantrell, D. Protein kinase C and beyond. Nat Immunol 5, 785–790 (2004). https://doi.org/10.1038/ni1097
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DOI: https://doi.org/10.1038/ni1097
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