The Novel PKCθ from Benchtop to Clinic

Journal of Immunology Research

Volumn 2015, Issue , 2015, Pages

  Hage Sleiman, Rouba ^a   Hamze, Asmaa B ^b   Reslan, Lina ^a   Kobeissy, Hadile ^a   Dbaibo, Ghassan ^a  

^a AMERICAN UNIVERSITY OF BEIRUT   (Lebanon)

^b GLOBAL UNIVERSITY   (Lebanon)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 2; ISOENZYME; PROTEIN KINASE C; PROTEIN KINASE C INHIBITOR; PROTEIN SERINE THREONINE KINASE; T LYMPHOCYTE RECEPTOR; LYMPHOCYTE ANTIGEN RECEPTOR;

ANTIGEN PRESENTING CELL; ARTICLE; AUTOIMMUNE DISEASE; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; ENZYME ACTIVE SITE; HINGE REGION; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL SYNAPSE; INFLAMMATION; LIPID RAFT; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN DOMAIN; PROTEIN FAMILY; PROTEIN INTERACTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; UBIQUITINATION; ANIMAL; IMMUNOLOGY; METABOLISM;

ANIMALS; ANTIGEN-PRESENTING CELLS; AUTOIMMUNE DISEASES; HUMANS; INFLAMMATION; ISOENZYMES; PROTEIN KINASE C; RECEPTORS, ANTIGEN, T-CELL; T-LYMPHOCYTES;

EID: 84930959593     PISSN: 23148861     EISSN: 23147156     Source Type: Journal    
DOI: 10.1155/2015/348798     Document Type: Article

References (215)

1. A. C. Newton, "Protein kinase C: structure, function, and regulation," Journal of Biological Chemistry, vol. 270, no. 48, pp. 28495-28498, 1995.
2. A. Bononi, C. Agnoletto, E. De Marchi et al., "Protein kinases and phosphatases in the control of cell fate," Enzyme Research, vol. 2011, Article ID 329098, 26 pages, 2011.
3. J. D. Chang, Y. Xu, M. K. Raychowdhury, and J. A. Ware, "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,"The Journal of Biological Chemistry, vol. 268, no. 19, pp. 14208-14214, 1993.
4. C. R. F. Monks, H. Kupfer, I. Tamir, A. Barlow, and A. Kupfer, "Selective modulation of protein kinase C-θ during T-cell activation," Nature, vol. 385, no. 6611, pp. 83-86, 1997.
5. A. Zanin-Zhorov, M. L. Dustin, and B. R. Blazar, "PKC-theta function at the immunological synapse: prospects for therapeutic targeting," Trends in Immunology, vol. 32, no. 8, pp. 358-363, 2011.
6. M. Inoue, A. Kishimoto, Y. Takai, and Y. Nishizuka, "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, vol. 252, no. 21, pp. 7610-7616, 1977.
7. Y. Takai, A. Kishimoto, U. Kikkawa, T. Mori, and Y. Nishizuka, "Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid-dependent protein kinase system," Biochemical and Biophysical Research Communications, vol. 91, no. 4, pp. 1218-1224, 1979.
8. G. Y. Kim, P. Nigro, K. Fujiwara, J. Abe, and B. C. Berk, "p62 binding to protein kinase C ζ regulates tumor necrosis factor α-induced apoptotic pathway in endothelial cells," Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32,no. 12, pp. 2974-2980, 2012.
9. A. C. Newton, "Protein kinase C: poised to signal," The American Journal of Physiology - Endocrinology and Metabolism, vol. 298, no. 3, pp. E395-E402, 1993.
10. Y. Pu, M. L. Peach, S. H. Garfield, S. Wincovitch, V. E. Marquez, and P. M. Blumberg, "Effects on ligand interaction and membrane translocation of the positively charged arginine residues situated along the C1 domain binding cleft in the atypical protein kinase C isoforms," The Journal of Biological Chemistry, vol. 281, no. 44, pp. 33773-33788, 2006.
11. H. Mellor and P. J. Parker, "The extended protein kinase C superfamily," Biochemical Journal, vol. 332, part 2, pp. 281-292, 1998.
12. Y. Nishizuka, "Protein kinase C and lipid signaling for sustained cellular responses," The FASEB Journal, vol. 9, no.7, pp. 484-496, 1995.
13. A. C. Newton, "Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions," Chemical Reviews, vol. 101, no. 8, pp. 2353-2364, 2001.
14. D. R. Knighton, J. H. Zheng, L. F. ten Eyck et al., "Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase," Science, vol. 253, no. 5018, pp. 407-414, 1991.
15. S. S. Taylor and E. Radzio-Andzelm, "Three protein kinase structures define a common motif," Structure, vol. 2, no. 5, pp. 345-355, 1994.
16. A. C. Newton, "Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm," Biochemical Journal, vol. 370, part 2, pp. 361-371, 2003.
17. A. Toker and A. C. Newton, "Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site," Journal of Biological Chemistry, vol. 275, no. 12, pp. 8271-8274, 2000.
18. E. M. Dutil, A. Toker, and A. C. Newton, "Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1)," Current Biology, vol. 8, no. 25, pp. 1366-1375, 1998.
19. J. A. Le Good, W. H. Ziegler, D. B. Parekh, D. R. Alessi, P. Cohen, and P. J. Parker, "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1," Science, vol. 281, no. 5385, pp. 2042-2045, 1998.
20. M. M. Chou, W. Hou, J. Johnson et al., "Regulation of protein kinase C zeta by PI 3-kinase and PDK-1," Current Biology, vol. 8, no. 19, pp. 1069-1077, 1998.
21. E. D. Sonnenburg, T. Gao, and A. C. Newton, "The phosphoinositide-dependent kinase, PDK-1, phosphorylates conventional protein kinase C isozymes by a mechanism that is independent of phosphoinositide 3-kinase," Journal of Biological Chemistry, vol. 276, no. 48, pp. 45289-45297, 2001.
22. P. Storz and A. Toker, "3′-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling," Frontiers in Bioscience, vol. 7, pp. d886-d902, 2002.
23. A. Balendran, G. R. Hare, A. Kieloch, M. R. Williams, and D. R. Alessi, "Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms," The FEBS Letters, vol. 484, no. 3, pp. 217-223, 2000.
24. A. Behn-Krappa and A. C. Newton, "The hydrophobic phosphorylation motif of conventional protein kinase C is regulated by autophosphorylation," Current Biology, vol. 9, no. 14, pp. 728-737, 1999.
25. D. Parekh, W. Ziegler, K. Yonezawa, K. Hara, and P. J. Parker, "Mammalian TOR controls one of two kinase pathways acting upon nPKCδ and nPKCε," Journal of Biological Chemistry, vol. 274, no. 49, pp. 34758-34764, 1999.
26. W. H. Ziegler, D. B. Parekh, J. A. Le Good et al., "Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex," Current Biology, vol. 9, no. 10, pp. 522-529, 1999.
27. Y. Liu, C. Graham, A. Li, R. J. Fisher, and S. Shaw, "Phosphorylation of the protein kinase C-theta 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, vol. 361, no. 2, pp. 255-265, 2002.
28. F. Bornancin and P. J. Parker, "Phosphorylation of protein kinase C-α on serine 657 controls the accumulation of active enzyme and contributes to its phosphatase-resistant state," The Journal of Biological Chemistry, vol. 272, no. 6, pp. 3544-3549, 1997.
29. A. S. Edwards and A. C. Newton, "Phosphorylation at conserved carboxyl-terminal hydrophobic motif regulates the catalytic and regulatory domains of protein kinase C," Journal of Biological Chemistry, vol. 272, no. 29, pp. 18382-18390, 1997.
30. T. Gao, A. Toker, and A. C. Newton, "The carboxyl terminus of protein kinase c provides a switch to regulate its interaction with the phosphoinositide-dependent kinase, PDK-1," The Journal of Biological Chemistry, vol. 276, no. 22, pp. 19588-19596, 2001.
31. T. Ikenoue, K. Inoki, Q. Yang, X. Zhou, and K. L. Guan, "Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling," The EMBO Journal, vol. 27, no. 14, pp. 1919-1931, 2008.
32. J. W. Orr and A. C. Newton, "Requirement for negative charge on 'activation loop' of protein kinase C," The Journal of Biological Chemistry, vol. 269, no. 44, pp. 27715-27718, 1994.
33. C. House and B. E. Kemp, "Protein kinase C contains a pseudosubstrate prototope in its regulatory domain," Science, vol. 238, no. 4834, pp. 1726-1728, 1987.
34. D. Ron and M. G. Kazanietz, "New insights into the regulation of protein kinase C and novel phorbol ester receptors," The FASEB Journal, vol. 13, no. 13, pp. 1658-1676, 1999.
35. E. M. Dutil and A. C. Newton, "Dual role of pseudosubstrate in the coordinated regulation of protein kinase C by phosphorylation and diacylglycerol," The Journal of Biological Chemistry, vol. 275, no. 14, pp. 10697-10701, 2000.
36. D. Ron, C.-H. Chen, J. Caldwell, L. Jamieson, E. Orr, and D. Mochly-Rosen, "Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins," Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 3, pp. 839-843, 1994.
37. D. Mochly-Rosen and A. S. Gordon, "Anchoring proteins for protein kinase C: a means for isozyme selectivity," The FASEB Journal, vol. 12, no. 1, pp. 35-42, 1998.
38. N. Oka, M. Yamamoto, C. Schwencke et al., "Caveolin interaction with protein kinase C. Isoenzyme-dependent regulation of kinase activity by the caveolin scaffolding domain peptide," Journal of Biological Chemistry, vol. 272, no. 52, pp. 33416-33421, 1997.
39. T. M. Klauck, M. C. Faux, K. Labudda, L. K. Langeberg, S. Jaken, and J. D. Scott, "Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein," Science, vol. 271, no. 5255, pp. 1589-1592, 1996.
40. T. Gao, J. Brognard, and A. C. Newton, "The phosphatase PHLPP controls the cellular levels of protein kinase C," Journal of Biological Chemistry, vol. 283, no. 10, pp. 6300-6311, 2008.
41. E. M. Dutil, L. M. Keranen, A. A. DePaoli-Roach, and A. C. Newton, "In vivo regulation of protein kinase C by transphosphorylation followed by autophosphorylation," The Journal of Biological Chemistry, vol. 269, no. 47, pp. 29359-29362, 1994.
42. J. Brognard and A. C. Newton, "PHLiPPing the switch on Akt and protein kinase C signaling," Trends in Endocrinology & Metabolism, vol. 19, no. 6, pp. 223-230, 2008.
43. J. H. Ahn, T. McAvoy, S. V. Rakhilin, A. Nishi, P. Greengard, and A. C. Nairn, "Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit," Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 8, pp. 2979-2984, 2007.
44. E. Sontag, J.-M. Sontag, and A. Garcia, "Protein phosphatase 2A is a critical regulator of protein kinase C ζ signaling targeted by SV40 small t to promote cell growth and NF-κB activation," The EMBO Journal, vol. 16, no. 18, pp. 5662-5671, 1997.
45. A. C. Eitelhuber, S. Warth, G. Schimmack et al., "Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation," The EMBO Journal, vol. 30, no. 3, pp. 594-605, 2011.
46. D. J. Katzmann, G. Odorizzi, and S. D. Emr, "Receptor downregulation and multivesicular-body sorting," Nature Reviews Molecular Cell Biology, vol. 3, no. 12, pp. 893-905, 2002.
47. E. S. Seto, H. J. Bellen, and T. E. Lloyd, "When cell biology meets development: endocytic regulation of signaling pathways," Genes and Development, vol. 16, no. 11, pp. 1314-1336, 2002.
48. Z. Lu, D. Liu, A. Hornia, W. Devonish, M. Pagano, and D. A. Foster, "Activation of protein kinase C triggers its ubiquitination and degradation," Molecular and Cellular Biology, vol. 18, no. 2, pp. 839-845, 1998.
49. D. Schechtman and D. Mochly-Rosen, "Adaptor proteins in protein kinase C-mediated signal transduction," Oncogene, vol. 20, no. 44, pp. 6339-6347, 2001.
50. G. Baier, D. Telford, L. Giampa et al., "Molecular cloning and characterization of PKCtheta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells,"The Journal of Biological Chemistry, vol. 268, no. 7, pp. 4997-5004, 1993.
51. D. J. Burns and R. M. Bell, "Protein kinase C contains two phorbol ester binding domains," The Journal of Biological Chemistry, vol. 266, no. 27, pp. 18330-18338, 1991.
52. H. R. Melowic, R. V. Stahelin, N. R. Blatner et al., "Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Ctheta," Journal of Biological Chemistry, vol. 282, no. 29, pp. 21467-21476, 2007.
53. K.-F. Kong, T. Yokosuka, A. J. Canonigo-Balancio, N. Isakov, T. Saito, and A. Altman, "A motif in the V3 domain of the kinase PKC-theta determines its localization in the immunological synapse and functions in T cells via association with CD28," Nature Immunology, vol. 12, no. 11, pp. 1105-1112, 2011.
54. N. Isakov and A. Altman, "PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors," Frontiers in Immunology, vol. 3, article 273, 2012.
55. Z. B. Xu, D. Chaudhary, S. Olland et al., "Catalytic domain crystal structure of protein kinase C-theta (PKCtheta)," The Journal of Biological Chemistry, vol. 279, no. 48, pp. 50401-50409, 2004.
56. Y. Yang and T. I. Igumenova, "The C-terminal V5 domain of Protein Kinase Cα is intrinsically disordered, with propensity to associate with a membrane mimetic," PLoS ONE, vol. 8, no. 6, Article ID e65699, 2013.
57. N. Meller, Y. C. Liu, T. L. Collins et al., "Direct interaction between protein kinase C theta (PKC theta) and 14-3-3 tau in T cells: 14-3-3 overexpression results in inhibition of PKC theta translocation and function," Molecular and Cellular Biology, vol. 16, no. 10, pp. 5782-5791, 1996.
58. P. L. Schwartzberg, K. L. Mueller, H. Qi, and J. L. Cannons, "SLAM receptors and SAP influence lymphocyte interactions, development and function," Nature Reviews Immunology, vol. 9, no. 1, pp. 39-46, 2009.
59. H2 differentiation and PKC-θ-mediated activation of NF-κB1," Immunity, vol. 21, no. 5, pp. 693-706, 2004.
60. J. L. Cannons, J. Z. Wu, J. Gomez-Rodriguez et al., "Biochemical and genetic evidence for a SAP-PKC-theta interaction contributing to IL-4 regulation," The Journal of Immunology, vol. 185, no. 5, pp. 2819-2827, 2010.
61. C. Krawczyk, K. Bachmaier, T. Sasaki et al., "Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells," Immunity, vol. 13, no. 4, pp. 463-473, 2000.
62. T. Gruber, N. Hermann-Kleiter, R. Hinterleitner et al., "PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation," Science Signaling, vol. 2, no. 76, p. ra30, 1954.
63. Y.-Y. Kong, K.-D. Fischer, M. F. Bachmann et al., "Vav regulates peptide-specific apoptosis in thymocytes," Journal of Experimental Medicine, vol. 188, no. 11, pp. 2099-2111, 1998.
64. O. Dienz, S. P. Hehner, W. Droge, and M. L. Schmitz, "Synergistic activation of NF-κB by functional cooperation between Vav and PKCθ in T lymphocytes," The Journal of Biological Chemistry, vol. 275, no. 32, pp. 24547-24551, 2000.
65. M. Villalba, N. Coudronniere, M. Deckert, E. Teixeiro, P. Mas, and A. Altman, "A novel functional interaction between Vav and PKCθ is required for TCR-induced T cell activation," Immunity, vol. 12, no. 2, pp. 151-160, 2000.
66. M. Ishida, T. Itsukaichi, D. Kobayashi, and H. Kikuchi, "Alteration of the PKC theta-Vav1 complex and phosphorylation of Vav1 in TCDD-induced apoptosis in the lymphoblastic T cell line," Toxicology, vol. 275, no. 1-3, pp. 72-78, 2010.
67. R. Matsumoto, D. Wang, M. Blonska et al., "Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-κB activation," Immunity, vol. 23, no. 6, pp. 575-585, 2005.
68. H. Jono, J. H. Lim, H. Xu, and J. D. Li, "PKCtheta synergizes with TLR-dependent TRAF6 signaling pathway to upregulate MUC5AC mucin via CARMA1," PLoS ONE, vol. 7, no. 1, Article ID e31049, 2012.
69. + T cell activation," Immunology Letters, vol. 126, no. 1-2, pp. 54-59, 2009.
70. F. Zappelli, D. Willems, S.-I. Osada et al., "The inhibition of differentiation caused by TGFβ in fetal myoblasts is dependent upon selective expression of PKCθ: a possible molecular basis for myoblast diversification during limb histogenesis," Developmental Biology, vol. 180, no. 1, pp. 156-164, 1996.
71. R. Paoletti, A. Maffei, L. Madaro et al., "Protein kinase Ctheta is required for cardiomyocyte survival and cardiac remodeling," Cell Death and Disease, vol. 1, no. 5, article e45, 2010.
72. L. Madaro, V. Marrocco, P. Fiore et al., "PKCθ signaling is required for myoblast fusion by regulating the expression of caveolin-3 and β1D integrin upstream focal adhesion kinase," Molecular Biology of the Cell, vol. 22, no. 8, pp. 1409-1419, 2011.
73. J. Liliental and D. D. Chang, "Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit," The Journal of Biological Chemistry, vol. 273, no. 4, pp. 2379-2383, 1998.
74. S. Tang, Y. Gao, and J. A. Ware, "Enhancement of endothelial cell migration and in vitro tube formation by TAP20, a novel beta 5 integrin-modulating, PKC theta-dependent protein," The Journal of Cell Biology, vol. 147, no. 5, pp. 1073-1084, 1999.
75. I. Michalczyk, A. F. Sikorski, L. Kotula, R. P. Junghans, and P. M. Dubielecka, "The emerging role of protein kinase Cθ in cytoskeletal signaling," Journal of Leukocyte Biology, vol. 93, no. 3, pp. 319-327, 2013.
76. T. Letschka, V. Kollmann, C. Pfeifhofer-Obermair et al., "PKCtheta selectively controls the adhesion-stimulating molecule Rap1," Blood, vol. 112, no. 12, pp. 4617-4627, 2008.
77. J.-I. Suzuki, S. Yamasaki, J. Wu, G. A. Koretzky, and T. Saito, "The actin cloud induced by LFA-1-mediated outside-in signals lowers the threshold for T-cell activation," Blood, vol. 109, no. 1, pp. 168-175, 2007.
78. J. C. Porter, M. Bracke, A. Smith, D. Davies, and N. Hogg, "Signaling through integrin LFA-1 leads to filamentous actin polymerization and remodeling, resulting in enhanced T cell adhesion," Journal of Immunology, vol. 168, no. 12, pp. 6330-6335, 2002.
79. M. Huse, "Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond," Frontiers in Immunology, vol. 3, p. 235, 2012.
80. E. J. Quann, X. Liu, G. Altan-Bonnet, and M. Huse, "A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells," Nature Immunology, vol. 12, no. 7, pp. 647-654, 2011.
81. P. M. Dubielecka, M. Grzybek, A. Kolondra et al., "Aggregation of spectrin and PKCtheta is an early hallmark of fludarabine/mitoxantrone/dexamethasone-induced apoptosis in Jurkat T and HL60 cells," Molecular and Cellular Biochemistry, vol. 339, no. 1-2, pp. 63-77, 2010.
82. A. Banan, L. J. Zhang, M. Shaikh, J. Z. Fields, A. Farhadi, and A. Keshavarzian, "θ-isoform of PKC is required for alterations in cytoskeletal dynamics and barrier permeability in intestinal epithelium: a novel function for PKC-θ," American Journal of Physiology - Cell Physiology, vol. 287, no. 1, pp. C218-C234, 2004.
83. M. Villalba and A. Altman, "Protein kinase C-θ (PKCθ), a potential drug target for therapeutic intervention with human T cell leukemias," Current Cancer Drug Targets, vol. 2, no. 2, pp. 125-134, 2002.
84. W. R. Burack, K. H. Lee, A. D. Holdorf, M. L. Dustin, and A. S. Shaw, "Cutting edge: quantitative imaging of raft accumulation in the immunological synapse,"The Journal of Immunology, vol. 169, no. 6, pp. 2837-2841, 2002.
85. J. Huang, P. F. Lo, T. Zal et al., "CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse," Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 14, pp. 9369-9373, 2002.
86. T. Yokosuka, W. Kobayashi, K. Sakata-Sogawa et al., "Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters and protein kinase C theta translocation," Immunity, vol. 29, no. 4, pp. 589-601, 2008.
87. A. Altman and M. Villalba, "Protein kinase C-θ (PKCθ): it's all about location, location, location," Immunological Reviews, vol. 192, no. 1, pp. 53-63, 2003.
88. K. Bi, Y. Tanaka, N. Coudronniere et al., "Antigen-induced translocation of PKC-theta to membrane rafts is required for T cell activation," Nature Immunology, vol. 2, no. 6, pp. 556-563, 2001.
89. M. Villalba, K. Bi, J. Hu 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, vol. 157, no. 2, pp. 253-263, 2002.
90. N. G. Cartwright, A. K. Kashyap, and B. C. Schaefer, "An active kinase domain is required for retention of PKCtheta at the T cell immunological synapse," Molecular Biology of the Cell, vol. 22, no. 18, pp. 3491-3497, 2011.
91. N. Coudronniere, M. Villalba, N. Englund, and A. Altman, "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, vol. 97, no. 7, pp. 3394-3399, 2000.
92. X. Lin, A. O'Mahony, Y. Mu, R. Geleziunas, and W. C. Greene, "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, vol. 20, no. 8, pp. 2933-2940, 2000.
93. A. Khoshnan, D. Bae, C. A. Tindell, and A. E. Nel, "The physical association of protein kinase Cθ with a lipid raft-associated inhibitor of κB factor kinase (IKK) complex plays a role in the activation of the NF-κB cascade by TCR and CD28," Journal of Immunology, vol. 165, no. 12, pp. 6933-6940, 2000.
94. A. Avraham, S. Jung, Y. Samuels, R. Seger, and Y. Ben-Neriah, "Co-stimulation-dependent activation of a JNK-kinase in T lymphocytes," European Journal of Immunology, vol. 28, no. 8, pp. 2320-2330, 1998.
95. 2+ mobilization and NFAT cell activation in primary mouse T cells," Journal of Experimental Medicine, vol. 197, no. 11, pp. 1525-1535, 2003.
96. 2+ signaling by PKCtheta in restimulated T cells via a Tec kinase-dependent pathway," European Journal of Immunology, vol. 34, no. 7, pp. 2001-2011, 2004.
97. J. W. Orr and A. C. Newton, "Interaction of protein kinase C with phosphatidylserine. 2. Specificity and regulation," Biochemistry, vol. 31, no. 19, pp. 4667-4673, 1992.
98. Y. Liu, S. Witte, Y.-C. Liu, M. Doyle, C. Elly, and A. Altman, "Regulation of protein kinase Cθ function during T cell activation by Lck-mediated tyrosine phosphorylation," Journal of Biological Chemistry, vol. 275, no. 5, pp. 3603-3609, 2000.
99. R. Tavano, G. Gri, B. Molon et al., "CD28 and lipid rafts coordinate recruitment of Lck to the immunological synapse of human T lymphocytes,"The Journal of Immunology, vol. 173, no. 9, pp. 5392-5397, 2004.
100. E. Hofinger, H. Sticht, R. Tavano, and A. Viola, "Multiple modes of interaction between Lck and CD28," Journal of Immunology, vol. 174, no. 7, pp. 3839-3840, 2005.
101. H.-C. Chuang, J.-L. Lan, D.-Y. Chen et al., "The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells," Nature Immunology, vol. 12, no. 11, pp. 1113-1118, 2011.
102. N. Thuille, I. Heit, F. Fresser et al., "Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes," The EMBO Journal, vol. 24, no. 22, pp. 3869-3880, 2005.
103. R. Czerwinski, A. Aulabaugh, R. M. Greco et al., "Characterization of protein kinase C theta activation loop autophosphorylation and the kinase domain catalytic mechanism," Biochemistry, vol. 44, no. 28, pp. 9563-9573, 2005.
104. B. Nolen, S. Taylor, and G. Ghosh, "Regulation of protein kinases; controlling activity through activation segment conformation," Regulation of protein kinases, vol. 15, pp. 661-675, 2004.
105. A. Messerschmidt, S. Macieira, M. Velarde et al., "Crystal structure of the catalytic domain of human atypical protein kinase C-iota reveals interaction mode of phosphorylation site in turn motif," Journal of Molecular Biology, vol. 352, no. 4, pp. 918-931, 2005.
106. N. Grodsky, Y. Li, D. Bouzida et al., "Structure of the catalytic domain of human protein kinase C β II complexed with a bisindolylmaleimide inhibitor," Biochemistry, vol. 45, no. 47, pp. 13970-13981, 2006.
107. K. Lee, P. Gudapati, S. Dragovic et al., "Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways," Immunity, vol. 32, no. 6, pp. 743-753, 2010.
108. M. Freeley, Y. Volkov, D. Kelleher, and A. Long, "Stimulus-induced phosphorylation of PKC theta at the C-terminal hydrophobic-motif in human T lymphocytes," Biochemical and Biophysical Research Communications, vol. 334, no. 2, pp. 619-630, 2005.
109. V. Heissmeyer, F. Macián, S.-H. Im et al., "Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins," Nature Immunology, vol. 5, no. 3, pp. 255-265, 2004.
110. S. Vardhana, K. Choudhuri, R. Varma, and M. L. Dustin, "Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster," Immunity, vol. 32, no. 4, pp. 531-540, 2010.
111. E. Y. Zhang, K. F. Kong, and A. Altman, "The yin and yang of protein kinase C-theta (PKCtheta): a novel drug target for selective immunosuppression," Advances in Pharmacology, vol. 66, pp. 267-312, 2013.
112. S. Sakaguchi, T. Yamaguchi, T. Nomura, and M. Ono, "Regulatory T cells and immune tolerance," Cell, vol. 133, no. 5, pp. 775-787, 2008.
113. A. Zanin-Zhorov, Y. Ding, S. Kumari et al., "Protein kinase C-theta mediates negative feedback on regulatory T cell function," Science, vol. 328, no. 5976, pp. 372-376, 2010.
114. M.-J. Kwon, R. Wang, J. Ma, and Z. Sun, "PKC-theta is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection," Endocrine, Metabolic & Immune Disorders Drug Targets, vol. 10, no. 4, pp. 367-372, 2010.
115. Y.-M. Chen, H.-C. Chuang, W.-C. Lin et al., "Germinal center kinase-like kinase overexpression in T cells as a novel biomarker in rheumatoid arthritis," Arthritis & Rheumatism, vol. 65,no. 10, pp. 2573-2582, 2013.
116. A. M. Healy, E. Izmailova, M. Fitzgerald et al., "PKC-theta-deficient mice are protected from th1-dependent antigen-induced arthritis," Journal of Immunology, vol. 177, no. 3, pp. 1886-1893, 2006.
117. S. Salek-Ardakani, T. So, B. S. Halteman, A. Altman, and M. Croft, "Protein kinase Cθ controls Th1 cells in experimental autoimmune encephalomyelitis," The Journal of Immunology, vol. 175, no. 11, pp. 7635-7641, 2005.
118. S.-L. Tan, J. Zhao, C. Bi et al., "Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase Cθ-deficient mice," The Journal of Immunology, vol. 176, no. 5, pp. 2872-2879, 2006.
119. K. Anderson, M. Fitzgerald, M. DuPont et al., "Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases," Autoimmunity, vol. 39, no. 6, pp. 469-478, 2006.
120. X. Fang, R. Wang, J. Ma, Y. Ding, W. Shang, and Z. Sun, "Ameliorated ConA-induced hepatitis in the absence of PKC-theta," PLoS ONE, vol. 7, no. 2, Article ID e31174, 2012.
121. Z. Sun, "Intervention of PKC-θ as an immunosuppressive regimen," Frontiers in Immunology, vol. 3, p. 225, 2012.
122. B. J. Marsland, C. Nembrini, K. Grün et al., "TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote autoimmune myocarditis," Journal of Immunology, vol. 178, no. 6, pp. 3466-3473, 2007.
123. M. J. Kwon, J. Ma, Y. Ding, R. Wang, and Z. Sun, "Protein kinase C-theta promotes Th17 differentiation via upregulation of Stat3," The Journal of Immunology, vol. 188, no. 12, pp. 5887-5897, 2012.
124. B. J. Marsland, T. J. Soos, G. Späth, D. R. Littman, and M. Kopf, "Protein kinase Cθ is critical for the development of in vivo T helper (Th)2 cell but not Th-1 cell responses," The Journal of Experimental Medicine, vol. 200, no. 2, pp. 181-189, 2004.
125. S. Salek-Ardakani, T. So, B. S. Halteman, A. Altman, and M. Croft, "Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase Cθ," Journal of Immunology, vol. 173, no. 10, pp. 6440-6447, 2004.
126. J. O. Valenzuela, C. Iclozan, M. S. Hossain et al., "PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice," The Journal of Clinical Investigation, vol. 119, no. 12, pp. 3774-3786, 2009.
127. S. Manicassamy, D. Yin, Z. Zhang, L. L. Molinero, M. L. Alegre, and Z. Sun, "A Critical role for protein kinase C-theta-mediated T cell survival in cardiac allograft rejection," Journal of Immunology, vol. 181, no. 1, pp. 513-520, 2008.
128. C. C. Bronk, X.-Z. Yu, and A. A. Beg, "Targeting PKCθ in alloreactivity and graft-versus-host-disease: unanswered questions and therapeutic potential," Frontiers in Immunology, vol. 3, p. 259, 2012.
129. C. L. Willis, D. S. Meske, and T. P. Davis, "Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation," Journal of Cerebral Blood Flow and Metabolism, vol. 30, no. 11, pp. 1847-1859, 2010.
130. R. R. Rigor, R. S. Beard Jr., O. P. Litovka, and S. Y. Yuan, "Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium," The American Journal of Physiology - Cell Physiology, vol. 302, no. 10, pp. C1513-C1522, 2012.
131. D. V. N. Kumar, J. Shanmugasundaram, C. Sundaram, and M. P. J. S. Anandaraj, "Activity of novel protein kinase C and distribution of protein kinase Cθ in subcellular fractions of normal and Duchenne muscular dystrophic muscle," Indian Journal of Biochemistry and Biophysics, vol. 39, no. 6, pp. 377-381, 2002.
132. L. Madaro, A. Pelle, C. Nicoletti et al., "PKC theta ablation improves healing in a mouse model of muscular dystrophy," PLoS ONE, vol. 7, no. 2, Article ID e31515, 2012.
133. M. Villalba, P. Bushway, and A. Altman, "Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD," Journal of Immunology, vol. 166, no. 10, pp. 5955-5963, 2001.
134. M. P. Felli, A. Vacca, A. Calce et al., "PKCtheta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia," Oncogene, vol. 24, no. 6, pp. 992-1000, 2005.
135. S. Checquolo, R. Palermo, S. Cialfi et al., "Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia," Oncogene, vol. 29, no. 10, pp. 1463-1474, 2010.
136. K. Belguise and G. E. Sonenshein, "PKCtheta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor α synthesis," Journal of Clinical Investigation, vol. 117, no. 12, pp. 4009-4021, 2007.
137. K. Belguise, S. Milord, F. Galtier, G. Moquet-Torcy, M. Piechaczyk, and D. Chalbos, "The PKCθ pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells," Oncogene, vol. 31, no. 47, pp. 4889-4897, 2012.
138. P. Blay, A. Astudillo, J. M. Buesa et al., "Protein kinase Cθ is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias," Clinical Cancer Research, vol. 10, no. 12, pp. 4089-4095, 2004.
139. A. Duensing, N. E. Joseph, F. Medeiros et al., "Protein kinase Cθ (PKCθ) expression and constitutive activation in gastrointestinal stromal tumors (GISTs)," Cancer Research, vol. 64, no. 15, pp. 5127-5131, 2004.
140. L. Madaro, V. Marrocco, S. Carnio, M. Sandri, and M. Bouché, "Intracellular signaling in ER stress-induced autophagy in skeletalmuscle cells," The FASEB Journal, vol. 27,no. 5, pp. 1990-2000, 2013.
141. G. H. Kang, A. Srivastava, Y. E. Kim et al., "DOG1 and PKC-theta are useful in the diagnosis of KIT-negative gastrointestinal stromal tumors," Modern Pathology, vol. 24, no. 6, pp. 866-875, 2011.
142. R. Metz, S. Rust, J. B. DuHadaway et al., "IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan," OncoImmunology, vol. 1, no. 9, pp. 1460-1468, 2012.
143. 2+ ATPase (SERCA)," The Journal of Biological Chemistry, vol. 287, no. 39, pp. 32881-32896, 2012.
144. J. Garaude, S. Kaminski, S. Charni et al., "Impaired anti-leukemicimmune response in PKCtheta-deficient mice,"Molecular Immunology, vol. 45, no. 12, pp. 3463-3469, 2008.
145. J. I. Aguiló, J. Garaude, J. Pardo, M. Villalba, and A. Anel, "Protein kinase C-theta is required for NK cell activation and in vivo control of tumor progression," Journal of Immunology, vol. 182, no. 4, pp. 1972-1981, 2009.
146. A. Anel, J. I. Aguiló, E. Catalán et al., "Protein kinase C-theta (PKC-theta) in natural killer cell function and anti-tumor immunity," Frontiers in Immunology, vol. 3, p. 187, 2012.
147. K. Krzewski, X. Chen, J. S. Orange, and J. L. Strominger, "Formation of a WIP-, WASp-, actin-, and myosin IIA - containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling," The Journal of Cell Biology, vol. 173, no. 1, pp. 121-132, 2006.
148. I. Tassi, M. Cella, R. Presti et al., "NK cell-activating receptors require PKC-theta for sustained signaling, transcriptional activation, and IFN-gamma secretion," Blood, vol. 112, no. 10, pp. 4109-4116, 2008.
149. X. Qu, J. P. Seale, and R. Donnelly, "Tissue and isoform-selective activation of protein kinase C in insulin-resistant obese Zucker rats - effects of feeding," Journal of Endocrinology, vol. 162, no. 2, pp. 207-214, 1999.
150. K. S. Bell, C. Schmitz-Peiffer, M. Lim-Fraser, T. J. Biden, G. J. Cooney, and E. W. Kraegen, "Acute reversal of lipid-induced muscle insulin resistance is associated with rapid alteration in PKC-theta localization," The American Journal of Physiology - Endocrinology and Metabolism, vol. 279, no. 5, pp. E1196-E1201, 2000.
151. M. E. Griffin, M. J. Marcucci, G. W. Cline et al., "Free fatty acid-induced insulin resistance is associated with activation of protein kinase Cθ and alterations in the insulin signaling cascade," Diabetes, vol. 48, no. 6, pp. 1270-1274, 2000.
152. C. Yu, Y. Chen, G. W. Cline et al., "Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle," Journal of Biological Chemistry, vol. 277, no. 52, pp. 50230-50236, 2002.
153. J. K. Kim, J. J. Fillmore, M. J. Sunshine et al., "PKC-theta knockout mice are protected from fat-induced insulin resistance," Journal of Clinical Investigation, vol. 114, no. 6, pp. 823-827, 2004.
154. Z. Gao, X. Zhang, A. Zuberi et al., "Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes," Molecular Endocrinology, vol. 18, no. 8, pp. 2024-2034, 2004.
155. D. Haasch, C. Berg, J. E. Clampit et al., "PKCtheta is a key player in the development of insulin resistance," Biochemical and Biophysical Research Communications, vol. 343, no. 2, pp. 361-368, 2006.
156. L. Yang, Z. Qian, H. Ji et al., "Inhibitory effect on protein kinase Cθ by Crocetin attenuates palmitate-induced insulin insensitivity in 3T3-L1 adipocytes," European Journal of Pharmacology, vol. 642, no. 1-3, pp. 47-55, 2010.
157. C. Wang, M. Liu, R. A. Riojas et al., "Protein kinase Cθ (PKCθ)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance," Journal of Biological Chemistry, vol. 284, no. 4, pp. 2038-2044, 2009.
158. S. Gray, I. Idris, K. R. Davis, and R. Donnelly, "Increased skeletal muscle expression of PKC-theta but not PKC-alpha mRNA in type 2 diabetes: inverse relationship with in-vivo insulin sensitivity," European Journal of Clinical Investigation, vol. 33, no. 11, pp. 983-987, 2003.
159. S. C. Benoit, C. J. Kemp, C. F. Elias et al., "Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents,"The Journal of Clinical Investigation, vol. 119, no. 9, pp. 2577-2589, 2009.
160. H. Le Stunff, N. Coant, S. Migrenne, and C. Magnan, "Targeting lipid sensing in the central nervous system: new therapy against the development of obesity and type 2 diabetes," Expert Opinion on Therapeutic Targets, vol. 17, no. 5, pp. 545-555, 2013.
161. H. Oh, S. Boghossian, D. A. York, and M. Park-York, "The effect of high fat diet and saturated fatty acids on insulin signaling in the amygdala and hypothalamus of rats," Brain Research, vol. 1537, pp. 191-200, 2013.
162. M. Park-York, S. Boghossian, H. Oh, and D. A. York, "PKCθ expression in the amygdala regulates insulin signaling, food intake and body weight," Obesity, vol. 21, no. 4, pp. 755-764, 2013.
163. D. Mochly-Rosen, K. Das, and K. V. Grimes, "Protein kinase C, an elusive therapeutic target?" Nature Reviews Drug Discovery, vol. 11, no. 12, pp. 937-957, 2012.
164. G. Manning, D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam, "The protein kinase complement of the human genome," Science, vol. 298, no. 5600, pp. 1912-1934, 2002.
165. P. M. Blumberg, N. Kedei, N. E. Lewin et al., "Wealth of opportunity - the C1 domain as a target for drug development," Current Drug Targets, vol. 9, no. 8, pp. 641-652, 2008.
166. R. Mandil, E. Ashkenazi, M. Blass et al., "Protein kinase Cα and protein kinase Cδ play opposite roles in the proliferation and apoptosis of glioma cells," Cancer Research, vol. 61, no. 11, pp. 4612-4619, 2001.
167. P. Geraldes and G. L. King, "Activation of protein kinase C isoforms and its impact on diabetic complications," Circulation Research, vol. 106, no. 8, pp. 1319-1331, 2010.
168. S. E. Wilkinson, P. J. Parker, and J. S. Nixon, "Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C," Biochemical Journal, vol. 294, no. 2, pp. 335-337, 1993.
169. M. W. Karaman, S. Herrgard, D. K. Treiber et al., "A quantitative analysis of kinase inhibitor selectivity," Nature Biotechnology, vol. 26, no. 1, pp. 127-132, 2008.
170. C. M. Seynaeve, M. G. Kazanietz, P. M. Blumberg, E. A. Sausville, and P. J. Worland, "Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue," Molecular Pharmacology, vol. 45, no. 6, pp. 1207-1214, 1994.
171. C. Monnerat, R. Henriksson, T. le Chevalier et al., "Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer," Annals of Oncology, vol. 15, no. 2, pp. 316-323, 2004.
172. J. Budworth and A. Gescher, "Differential inhibition of cytosolic and membrane-derived protein kinase C activity by staurosporine and other kinase inhibitors," FEBS Letters, vol. 362, no. 2, pp. 139-142, 1995.
173. J.-P. Evenou, J. Wagner, G. Zenke et al., "The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation," The Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 3, pp. 792-801, 2009.
174. J. Wagner, P. von Matt, R. Sedrani et al., "Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]-pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes," Journal of Medicinal Chemistry, vol. 52, no. 20, pp. 6193-6196, 2009.
175. G. Weckbecker, C. Pally, C. Beerli 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, vol. 23, no. 5, pp. 543-552, 2010.
176. Y. H. Fang, D. J. Joo, B. J. Lim et al., "AEB-071 versus tacrolimus monotherapy to prevent acute cardiac allograft rejection in the rat: a preliminary report," Transplantation Proceedings, vol. 42, no. 3, pp. 976-979, 2010.
177. S. Manicassamy, "Sotrastaurin, a protein kinase C inhibitor for the prevention of transplant rejection and treatment of psoriasis," Current Opinion in Investigational Drugs, vol. 10, no. 11, pp. 1225-1235, 2009.
178. J. M. Kovarik, P. Neuhaus, U. Cillo et al., "Sotrastaurin single-dose pharmacokinetics in de novo liver transplant recipients," Transplant International, vol. 24, no. 3, pp. 276-283, 2011.
179. M. Matz, M. Naik, M.-F. Mashreghi, P. Glander, H.-H. Neumayer, and K. Budde, "Evaluation of the novel protein kinase C inhibitor sotrastaurin as immunosuppressive therapy after renal transplantation," Expert Opinion on Drug Metabolism & Toxicology, vol. 7, no. 1, pp. 103-113, 2011.
180. K. W. Lee, G. K. Sang, H. P. Kim et al., "Enzastaurin, a protein kinase C beta inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells," Cancer Research, vol. 68, no. 6, pp. 1916-1926, 2008.
181. M. J. Robertson, B. S. Kahl, J. M. Vose et al., "Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma," Journal of Clinical Oncology, vol. 25, no. 13, pp. 1741-1746, 2007.
182. T. N. Kreisl, S. Kotliarova, J. A. Butman et al., "A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas," Neuro-Oncology, vol. 12, no. 2, pp. 181-189, 2010.
183. B. Glimelius, M. Lahn, S. Gawande et al., "A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer," Annals of Oncology, vol. 21, no. 5, pp. 1020-1026, 2010.
184. L. P. Aiello, L. Vignati, M. J. Sheetz et al., "Oral protein kinase c β inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the protein kinase c β inhibitor-diabetic retinopathy study and the protein kinase c β inhibitor-diabetic retinopathy study 2," Retina, vol. 31, no. 10, pp. 2084-2094, 2011.
185. M. J. Millward, C. House, D. Bowtell et al., "The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study," British Journal of Cancer, vol. 95, no. 7, pp. 829-834, 2006.
186. T. Fischer, R. M. Stone, D. J. DeAngelo et al., "Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3," Journal of Clinical Oncology, vol. 28, no. 28, pp. 4339-4345, 2010.
187. M. A. Carducci, L. Musib, M. S. Kies et al., "Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer," Journal of Clinical Oncology, vol. 24, no. 25, pp. 4092-4099, 2006.
188. E. Galanis and J. C. Buckner, "Enzastaurin in the treatment of recurrent glioblastoma: a promise that did not materialize," Journal of Clinical Oncology, vol. 28, no. 7, pp. 1097-1098, 2010.
189. R. P. Danis and M. J. Sheetz, "Ruboxistaurin: PKC-beta inhibition for complications of diabetes," Expert Opinion on Pharmacotherapy, vol. 10, no. 17, pp. 2913-2925, 2009.
190. M. K. Sun and D. L. Alkon, "Bryostatin-1: pharmacology and therapeutic potential as a CNS drug," CNS Drug Reviews, vol. 12, no. 1, pp. 1-8, 2006.
191. B.-F. Ruan and H.-L. Zhu, "The chemistry and biology of the bryostatins: potential PKC inhibitors in clinical development," Current Medicinal Chemistry, vol. 19, no. 16, pp. 2652-2664, 2012.
192. M. Fährmann, "Targeting protein kinase C (PKC) in physiology and cancer of the gastric cell system," Current Medicinal Chemistry, vol. 15, no. 12, pp. 1175-1191, 2008.
193. H. J. Mackay and C. J. Twelves, "Targeting the protein kinase C family: are we there yet?" Nature Reviews Cancer, vol. 7, no. 7, pp. 554-562, 2007.
194. G. C. Jayson, D. Crowther, J. Prendiville et al., "A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion," British Journal of Cancer, vol. 72, no. 2, pp. 461-468, 1995.
195. M. L. Varterasian, R. M. Mohammad, D. S. Eilender et al., "Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia," Journal of Clinical Oncology, vol. 16, no. 1, pp. 56-62, 1998.
196. M. L. Varterasian, R. M. Mohammad, M. S. Shurafa et al., "Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia," Clinical Cancer Research, vol. 6, no. 3, pp. 825-828, 2000.
197. D. J. Propper, V. Macaulay, K. J. O'Byrne et al., "A phase II study of bryostatin 1 in metastatic malignant melanoma," British Journal of Cancer, vol. 78, no. 10, pp. 1337-1341, 1998.
198. J. A. Zonder, A. F. Shields, M. Zalupski et al., "A Phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer," Clinical Cancer Research, vol. 7, no. 1, pp. 38-42, 2001.
199. J. A. Ajani, Y. Jiang, J. Faust et al., "A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma," Investigational New Drugs, vol. 24, no. 4, pp. 353-357, 2006.
200. S. Grant, W. D. Jarvis, P. S. Swerdlow et al., "Potentiation of the activity of 1-beta-D-arabinofuranosylcytosine by the protein kinase C activator bryostatin 1 in HL-60 cells: association with enhanced fragmentation of mature DNA," Cancer Research, vol. 52, no. 22, pp. 6270-6278, 1992.
201. A. T. McGown, G. Jayson, G. R. Pettit, M. S. Haran, T. H. Ward, and D. Crowther, "Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro," British Journal of Cancer, vol. 77, no. 2, pp. 216-220, 1998.
202. J. Vrana, Z. Wang, A. S. Rao et al., "Induction of apoptosis and differentiation by fludarabine in human leukemia cells (U937): interactions with the macrocyclic lactone bryostatin 1," Leukemia, vol. 13, no. 7, pp. 1046-1055, 1999.
203. S. Wang, C.-Y. Guo, A. Castillo, P. Dent, and S. Grant, "Effect of bryostatin 1 on taxol-induced apoptosis and cytotoxicity in human leukemia cells (U937)," Biochemical Pharmacology, vol. 56, no. 5, pp. 635-644, 1998.
204. P. A. Wender, J. L. Baryza, S. E. Brenner et al., "Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity," Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 17, pp. 6721-6726, 2011.
205. H. C. Swannie and S. B. Kaye, "Protein kinase C inhibitors," Current Oncology Reports, vol. 4, no. 1, pp. 37-46, 2002.
206. S. Chand, N. Mehta, M. S. Bahia, A. Dixit, and O. Silakari, "Protein kinase C-theta inhibitors: a novel therapy for inflammatory disorders," Current Pharmaceutical Design, vol. 18, no. 30, pp. 4725-4746, 2012.
207. C. L. Cywin, G. Dahmann, A. S. Prokopowicz III et al., "Discovery of potent and selective PKC-θ inhibitors," Bioorganic & Medicinal Chemistry Letters, vol. 17, no. 1, pp. 225-230, 2007.
208. R. G. Dushin, T. Nittoli, C. Ingalls et al., "Synthesis and PKCθ inhibitory activity of a series of 4-indolylamino-5-phenyl-3-pyridinecarbonitriles," Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 9, pp. 2461-2463, 2009.
209. D. H. Boschelli, D. Wang, A. S. Prashad et al., "Optimization of 5-phenyl-3-pyridinecarbonitriles as PKCtheta inhibitors," Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 13, pp. 3623-3626, 2009.
210. C. Niu, D. H. Boschelli, L. N. Tumey et al., "First generation 5-vinyl-3-pyridinecarbonitrile PKCtheta inhibitors," Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 20, pp. 5829-5832, 2009.
211. J. Shim, C. Eid, J. Lee, E. Liu, D. Chaudhary, and D. H. Boschelli, "Synthesis and PKCtheta inhibitory activity of a series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles," Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 23, pp. 6575-6577, 2009.
212. D. H. Boschelli, J. Subrath, C. Niu et al., "Optimization of 5-vinylaryl-3-pyridinecarbonitriles as PKCtheta inhibitors," Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 6, pp. 1965-1968, 2010.
213. B. Wu, D. H. Boschelli, J. Lee, X. Yang, and D. Chaudhary, "Second generation 4-(4-methyl-1H-indol-5-ylamino)-2-phenylthieno[2,3-b]pyridine-5-carbonitrile PKCtheta inhibitors," Bioorganic & Medicinal Chemistry Letters, vol. 19, no. 3, pp. 766-769, 2009.
214. L. Nathan Tumey, D. H. Boschelli, J. Lee, and D. Chaudhary, "2-Alkenylthieno[2,3-b]pyridine-5-carbonitriles: potent and 22selective inhibitors of PKCθ," Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 15, pp. 4420-4423, 2008.
215. D. H. Boschelli, B. Wu, A. C. B. Sosa et al., "Synthesis and PKCθ inhibitory activity of a series of 4-(indol-5-ylamino)thieno[2,3-b]pyridine-5-carbonitriles," Bioorganic & Medicinal Chemistry Letters, vol. 18, no. 9, pp. 2850-2853, 2008.