Protein kinase C, an elusive therapeutic target?

Nature Reviews Drug Discovery

Volumn 11, Issue 12, 2012, Pages 937-957

  Mochly Rosen, Daria ^a   Das, Kanad ^a   Grimes, Kevin V ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; 7 HYDROXYSTAUROSPORINE; ADENOSINE; APRINOCARSEN; BALANOL; BRYOSTATIN 1; CARBOPLATIN; DELCASERTIB; ENZASTAURIN; FLOSEQUINAN; INHALATION ANESTHETIC AGENT; INTRAVENOUS ANESTHETIC AGENT; MIDOSTAURIN; MYCOPHENOLIC ACID; PEMETREXED; PLACEBO; PROTEIN KINASE C; PROTEIN KINASE C ALPHA; PROTEIN KINASE C BETA; PROTEIN KINASE C DELTA; PROTEIN KINASE C EPSILON; PROTEIN KINASE C THETA; RILUZOLE; ROTTLERIN; RUBOXISTAURIN; SOTRASTAURIN; STAUROSPORINE; TAMOXIFEN; TOPOTECAN; UNINDEXED DRUG;

ACUTE GRAFT REJECTION; ACUTE GRANULOCYTIC LEUKEMIA; ACUTE HEART INFARCTION; ATHEROSCLEROSIS; BIPOLAR DISORDER; BIPOLAR MANIA; BRAIN CANCER; BREAST CANCER; CASTRATION RESISTANT PROSTATE CANCER; CELLULAR DISTRIBUTION; CEREBROVASCULAR ACCIDENT; COLORECTAL CANCER; COMPETITIVE INHIBITION; CONGESTIVE HEART FAILURE; CORONARY ARTERY BYPASS SURGERY; DIABETES MELLITUS; DIABETIC CARDIOMYOPATHY; DIABETIC MACULAR EDEMA; DIABETIC NEPHROPATHY; DIABETIC NEUROPATHY; DIABETIC RETINOPATHY; DRUG BINDING SITE; DRUG DOSE COMPARISON; DRUG MEGADOSE; DRUG SELECTIVITY; DRUG STRUCTURE; ENDOTHELIAL DYSFUNCTION; ENZYME ACTIVATION; ENZYME STRUCTURE; ESOPHAGUS CANCER; GASTROINTESTINAL SYMPTOM; GLIOBLASTOMA; GLIOMA; HEAD AND NECK CANCER; HEART ARRHYTHMIA; HEART DISEASE; HEART FAILURE; HEART HYPERTROPHY; HEART MUSCLE ISCHEMIA; HEMATOLOGIC MALIGNANCY; HIGH THROUGHPUT SCREENING; HUMAN; HYPERGLYCEMIA; ISCHEMIC HEART DISEASE; KIDNEY CANCER; KIDNEY CARCINOMA; LARGE CELL LYMPHOMA; LUNG EMBOLISM; LUNG NON SMALL CELL CANCER; MANTLE CELL LYMPHOMA; MELANOMA; MULTIPLE MYELOMA; MYALGIA; MYELODYSPLASTIC SYNDROME; MYELOID LEUKEMIA; NEOPLASM; NONHODGKIN LYMPHOMA; NONHUMAN; ORGAN TRANSPLANTATION; OVARY CANCER; PANCREAS CANCER; PERITONEUM CANCER; PRIORITY JOURNAL; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; RESTENOSIS; REVIEW; SARCOMA; STOMACH CANCER; THROMBOCYTE ACTIVATION; THROMBOCYTOPENIA; THROMBOEMBOLISM; UTERINE CERVIX CANCER; UTERUS CANCER; VEIN THROMBOSIS; VENOUS THROMBOEMBOLISM;

ANIMALS; BIPOLAR DISORDER; CLINICAL TRIALS AS TOPIC; DIABETES COMPLICATIONS; ENZYME ACTIVATION; HEART DISEASES; HUMANS; ISOENZYMES; NEOPLASMS; ORGAN TRANSPLANTATION; PROTEIN KINASE C; PROTEIN KINASE INHIBITORS;

EID: 84870772239     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3871     Document Type: Review

References (258)

1. Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein-kinase by tumor-promoting phorbo esters. J. Biol. Chem. 257, 7847-7851 (1982).
2. Geraldes, P. & King, G. L. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ. Res. 106, 1319-1331 (2010).
3. Toton, E., Ignatowicz, E., Skrzeczkowska, K. & Rybczynska, M. Protein kinase Cε as a cancer marker and target for anticancer therapy. Pharmacol. Rep. 63, 19-29 (2011).
4. Inagaki, K., Churchill, E. & Mochly-Rosen, D. Epsilon protein kinase C as a potential therapeutic target for the ischemic heart. Cardiovasc. Res. 70, 222-230 (2006).
5. Ferreira, J. C., Brum, P. C. & Mochly-Rosen, D. βIIPKC and εPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J. Mol. Cell. Cardiol. 51, 479-484 (2011).
6. Zanin-Zhorov, A., Dustin, M. L. & Blazar, B. R. PKC-θ function at the immunological synapse: prospects for therapeutic targeting. Trends Immunol. 32, 358-363 (2011).
7. Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319-324 (2011).
8. Zhang, D., Anantharam, V., Kanthasamy, A. & Kanthasamy, A. G. Neuroprotective effect of protein kinase Cλ inhibitor rottlerin in cell culture and animal models of Parkinson's disease. J. Pharmacol. Exp. Ther. 322, 913-922 (2007).
9. Garrido, J. L., Godoy, J. A., Alvarez, A., Bronfman, M. & Inestrosa, N. C. Protein kinase C inhibits amyloid β peptide neurotoxicity by acting on members of the Wnt pathway. FASEB J. 16, 1982-1984 (2002).
10. Manji, H. K. & Lenox, R. H. The nature of bipolar disorder. J. Clin. Psychiatry 61 (Suppl. 13), 42-57 (2000).
11. Zarate, C. A. & Manji, H. K. Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs 23, 569-582 (2009).
12. Maioli, E. & Valacchi, G. Rottlerin: bases for a possible usage in psoriasis. Curr. Drug Metab. 11, 425-430 (2010).
13. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912-1934 (2002).
14. Takai, Y., Kishimoto, A., Inoue, M. & Nishizuka, Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. 1. Purification and characterization of an active enzyme from bovine cerebellum. J. Biol. Chem. 252, 7603-7609 (1977).
15. Takai, Y., Kishimoto, A., Kikkawa, U., Mori, T. & Nishizuka, Y. Unsaturated diacylglycerol as a possible messenger for the activation of calcium-activated, phospholipid dependent protein-kinase system. Biochem. Biophys. Res. Commun. 91, 1218-1224 (1979).
16. Coussens, L. et al. Multiple, distinct forms of bovin and human protein-kinase C suggest diversity in cellular signaling pathway. Science 233, 859-866 (1986).
17. Ono, Y. et al. The structure, expression, and properties of additional members of the protein kinase C family. J. Biol. Chem. 263, 6927-6932 (1988).
18. Ono, Y. et al. Expression and properties of two types of protein kinase C: alternative splicing from a single gene. Science 236, 1116-1120 (1987).
19. Parker, P. J. et al. The complete primary structure of protein-kinase C - the phorbol ester receptor. Science 233, 853-859 (1986).
20. Hirai, T. & Chida, K. Protein kinase Cζ (PKCζ): activation mechanisms and cellular functions. J. Biochem. 133, 1-7 (2003).
21. Suzuki, A., Akimoto, K. & Ohno, S. Protein kinase Cλ/ι (PKCλ/ι): a PKC isotype essential for the development of multicellular organisms. J. Biochem. 133, 9-16 (2003).
22. Steinberg, S. F. Structural basis of protein kinase C isoform function. Physiol. Rev. 88, 1341-1378 (2008).
23. Persaud, S. D., Hoang, V., Huang, J. & Basu, A. Involvement of proteolytic activation of PKCλ in cisplatin-induced apoptosis in human small cell lung cancer H69 cells. Int. J. Oncol. 27, 149-154 (2005).
24. Newton, A. C. Protein kinase C: structure, function, and regulation. J. Biol. Chem. 270, 28495-28498 (1995).
25. Konishi, H. et al. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc. Natl Acad. Sci. USA 94, 11233-11237 (1997).
26. Konishi, H. et al. Phosphorylation sites of protein kinase Cλ in H2O2-treated cells and its activation by tyrosine kinase in vitro. Proc. Natl Acad. Sci. USA 98, 6587-6592 (2001).
27. Mochly-Rosen, D. Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science 268, 247-251 (1995).
28. Chen, L. et al. Opposing cardioprotective actions and parallel hypertrophic effects of λPKC and εPKC. Proc. Natl Acad. Sci. USA 98, 11114-11119 (2001).
29. Murriel, C. L. & Mochly-Rosen, D. Opposing roles of λ and ε PKC in cardiac ischemia and reperfusion: targeting the apoptotic machinery. Arch. Biochem. Biophys. 420, 246-254 (2003).
30. Basu, A. & Pal, D. Two faces of protein kinase Cλ: the contrasting roles of PKCλ in cell survival and cell death. ScientificWorldJournal 10, 2272-2284 (2010).
31. Michie, A. M. & Nakagawa, R. The link between PKCα regulation and cellular transformation. Immunol. Lett. 96, 155-162 (2005).
32. Ishii, H. et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKCβ inhibitor. Science 272, 728-731 (1996).
33. Simonis, G., Braun, M. U., Kirrstetter, M., Schon, S. P. & Strasser, R. H. Mechanisms of myocardial remodeling: ramiprilat blocks the expressional upregulation of protein kinase C ε in the surviving myocardium early after infarction. J. Cardiovasc. Pharmacol. 41, 780-787 (2003).
34. Bowling, N. et al. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 99, 384-391 (1999).
35. Palaniyandi, S. S., Sun, L., Ferreira, J. C. & Mochly-Rosen, D. Protein kinase C in heart failure: a therapeutic target? Cardiovasc. Res. 82, 229-239 (2009).
36. Koyanagi, T. et al. Pharmacological inhibition of epsilon PKC suppresses chronic inflammation in murine cardiac transplantation model. J. Mol. Cell. Cardiol. 43, 517-522 (2007).
37. Dempsey, E. C., Cool, C. D. & Littler, C. M. Lung disease and PKCs. Pharmacol. Res. 55, 545-559 (2007).
38. Li, J. & Gobe, G. Protein kinase C activation and its role in kidney disease. Nephrology 11, 428-434 (2006).
39. Tuttle, K. R. Protein kinase C β inhibition for diabetic kidney disease. Diabetes Res. Clin. Pract. 82 (Suppl. 1), 70-74 (2008).
40. Varin, M. M. et al. In Sjogren's syndrome, B lymphocytes induce epithelial cells of salivary glands into apoptosis through protein kinase Cλ activation. Autoimmun. Rev. 11, 252-258 (2012).
41. Bright, R. & Mochly-Rosen, D. The role of protein kinase C in cerebral ischemic and reperfusion injury. Stroke 36, 2781-2790 (2005).
42. Sun, M. K. & Alkon, D. L. Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. Pharmacol. Therap. 127, 66-77 (2010).
43. Alkon, D. L., Sun, M. K. & Nelson, T. J. PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends Pharmacol. Sci. 28, 51-60 (2007).
44. Sweitzer, S. M. et al. Protein kinase Cε and γ: involvement in formalin-induced nociception in neonatal rats. J. Pharmacol. Exp. Ther. 309, 616-625 (2004).
45. Ytrehus, K., Liu, Y. & Downey, J. M. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am. J. Physiol. 266, H1145-H1152 (1994).
46. Brooks, G. & Hearse, D. J. Role of protein kinase C in ischemic preconditioning: player or spectator? Circ. Res. 79, 627-630 (1996).
47. Churchill, E. N., Murriel, C. L., Chen, C. H., Mochly-Rosen, D. & Szweda, L. I. Reperfusion-induced translocation of λPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation. Circ. Res. 97, 78-85 (2005).
48. Churchill, E. N., Ferreira, J. C., Brum, P. C., Szweda, L. I. & Mochly-Rosen, D. Ischaemic preconditioning improves proteasomal activity and increases the degradation of λPKC during reperfusion. Cardiovasc. Res. 85, 385-394 (2010).
49. Pratschke, J., Weiss, S., Neuhaus, P. & Pascher, A. Review of nonimmunological causes for deteriorated graft function and graft loss after transplantation. Transpl. Int. 21, 512-522 (2008).
50. Tanaka, M. et al. Suppression of graft coronary artery disease by a brief treatment with a selective εPKC activator and a λPKC inhibitor in murine cardiac allografts. Circulation 110 (Suppl. II), 194-199 (2004).
51. Sarma, N. J., Tiriveedhi, V., Angaswamy, N. & Mohanakumar, T. Role of antibodies to self-antigens in chronic allograft rejection: potential mechanism and therapeutic implications. Hum. Immunol. 9 Jul 2012 [epub ahead of print].
52. Inagaki, K., Hahn, H. S., Dorn, G. W. & Mochly-Rosen, D. Additive protection of the ischemic heart ex vivo by combined treatment with λ-protein kinase C inhibitor and ε-protein kinase C activator. Circulation 108, 869-875 (2003).
53. Lee, M. R., Duan, W. & Tan, S. L. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin. Ther. Targets 12, 535-552 (2008).
54. Sledge, G. W. Jr & Gokmen-Polar, Y. Protein kinase C β as a therapeutic target in breast cancer. Semin. Oncol. 33, S15-S18 (2006).
55. Kim, J., Koyanagi, T. & Mochly-Rosen, D. PKCλ activation mediates angiogenesis via NADPH oxidase activity in PC 3 prostate cancer cells. Prostate 71, 946-954 (2011).
56. Bacher, N., Zisman, Y., Berent, E. & Livneh, E. 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, 126-133 (1991).
57. Krasnitsky, E. et al. PKCη is a novel prognostic marker in non-small cell lung cancer. Anticancer Res. 32, 1507-1513 (2012).
58. Kim, K. M. et al. PKCθ expression in gastrointestinal stromal tumor. Mod. Pathol. 19, 1480-1486 (2006).
59. Nishikawa, T., Edelstein, D. & Brownlee, M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int. Suppl. 77, S26-S30 (2000).
60. Bezy, O. et al. PKCλ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. J. Clin. Invest. 121, 2504-2517 (2011).
61. Manji, H. K. et al. Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications. J. Clin. Psychiatry 60 (Suppl. 2), 27-39; discussion 40-41, 113-116 (1999).
62. DiazGranados, N. & Zarate, C. A. Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr. Psychiatry Rep. 10, 510-519 (2008).
63. Einat, H., Yuan, P., Szabo, S. T., Dogra, S. & Manji, H. K. Protein kinase C inhibition by tamoxifen antagonizes manic-like behavior in rats: implications for the development of novel therapeutics for bipolar disorder. Neuropsychobiology 55, 123-131 (2007).
64. Wang, H. Y., Markowitz, P., Levinson, D., Undie, A. S. & Friedman, E. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J. Psychiatr. Res. 33, 171-179 (1999).
65. Wang, H. Y. & Friedman, E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol. Psychiatry 40, 568-575 (1996).
66. Sadeh, J. S. et al. Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch. Dermatol. 133, 747-750 (1997).
67. Nishino, N., Kitamura, N., Hashimoto, T. & Tanaka, C. Transmembrane signalling systems in the brain of patients with Parkinson's disease. Rev. Neurosci. 4, 213-222 (1993).
68. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127-132 (2008).
69. Sobhia, M. E., Grewal, B. K., Bhat, J., Rohit, S. & Punia, V. Protein kinase CßII in diabetic complications: survey of structural, biological and computational studies. Expert Opin. Ther. Targets 16, 325-344 (2012).
70. Wilkinson, S. E., Parker, P. J. & Nixon, J. S. Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. Biochem. J. 294, 335-337 (1993).
71. Lee, K. W. et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells. Cancer Res. 68, 1916-1926 (2008).
72. Gschwendt, M. et al. Rottlerin, a novel protein-kinase inhibitor. Biochem. Biophys. Res. Commun. 199, 93-98 (1994).
73. Soltoff, S. P. Rottlerin: an inappropriate and ineffective inhibitor of PKCλ. Trends Pharmacol. Sci. 28, 453-458 (2007).
74. Zimmermann, J. et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC). Arch. Pharm. 329, 371-376 (1996).
75. Cole, D. C. et al. Identification, characterization and initial hit to lead optimization of a series of 4 arylamino-3 pyridinecarbonitrile as protein kinase C0 (PKC0) inhibitors. J. Med. Chem. 51, 5958-5963 (2008).
76. Pande, V., Ramos, M. J. & Gago, F. The protein kinase inhibitor balanol: structure-activity relationships and structure-based computational studies. Anticancer Agents Med. Chem. 8, 638-645 (2008).
77. Noh, K. M., Hwang, J. Y., Shin, H. C. & Koh, J. Y. A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol. Dis. 7, 375-383 (2000).
78. Blumberg, P. M. In vitro studies on the mode of action of the phorbol esters, potent tumor promoters: part 1. Crit. Rev. Toxicol. 8, 153-197 (1980).
79. Blumberg, P. M. et al. Mechanism of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands. Biochem. Pharmacol. 33, 933-940 (1984).
80. Marquez, V. E. et al. The transition from a pharmacophore-guided approach to a receptor-guided approach in the design of potent protein kinase C ligands. Pharmacol. Ther. 82, 251-261 (1999).
81. Garcia-Bermejo, M. L. et al. Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCα. J. Biol. Chem. 277, 645-655 (2002).
82. Workman, P., Kaye, S. B. & Schwartsmann, G. Laboratory and phase I studies of new cancer drugs. Curr. Opin. Oncol. 4, 1065-1072 (1992).
83. Dowlati, A. et al. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B cell malignancies. Clin. Cancer Res. 9, 5929-5935 (2003).
84. Szallasi, Z. et al. Bryostatin 1 protects protein kinase C λ from down-regulation in mouse keratinocytes in parallel with its inhibition of phorbol ester-induced differentiation. Mol. Pharmacol. 46, 840-850 (1994).
85. Wender, P. A., Verma, V. A., Paxton, T. J. & Pillow, T. H. Function-oriented synthesis, step economy, and drug design. Accounts Chem. Res. 41, 40-49 (2008).
86. Shindo, M. et al. Toward the identification of selective modulators of protein kinase C (PKC) isozymes: establishment of a binding assay for PKC isozymes using synthetic C1 peptide receptors and identification of the critical residues involved in the phorbol ester binding. Bioorg. Med. Chem. 9, 2073-2081 (2001).
87. Wender, P. A. et al. Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity. Proc. Natl Acad. Sci. USA 108, 6721-6726 (2011).
88. Wender, P. A. et al. Inspirations from nature. New reactions, therapeutic leads, and drug delivery systems. Pure Appl. Chem. 75, 143-155 (2003).
89. Kraft, A. S., Anderson, W. B., Cooper, H. L. & Sando, J. J. Decrease in cytosolic calcium phospholipid-dependent protein-kinase activity following phorbol ester treatment of EL4 thymoma cells. J. Biol. Chem. 257, 3193-3196 (1982).
90. Disatnik, M. H., Buraggi, G. & Mochly-Rosen, D. Localization of protein kinase C isozymes in cardiac myocytes. Exp. Cell Res. 210, 287-297 (1994).
91. Mochly-Rosen, D., Henrich, C. J., Cheever, L., Khaner, H. & Simpson, P. C. A protein kinase C isozyme is translocated to cytoskeletal elements on activation. Cell Regul. 1, 693-706 (1990).
92. Budas, G. R., Churchill, E. N., Disatnik, M. H., Sun, L. & Mochly-Rosen, D. Mitochondrial import of PKCε is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury. Cardiovasc. Res. 88, 83-92 (2010).
93. Goodnight, J. A., Mischak, H., Kolch, W. & Mushinski, J. F. Immunocytochemical localization of eight protein kinase C isozymes overexpressed in NIH 3T3 fibroblasts. Isoform-specific association with microfilaments, Golgi, endoplasmic reticulum, and nuclear and cell membranes. J. Biol. Chem. 270, 9991-10001 (1995).
94. Kim, J. et al. Centrosomal PKCßII and pericentrin are critical for human prostate cancer growth and angiogenesis. Cancer Res. 68, 6831-6839 (2008).
95. Passalacqua, M., Patrone, M., Sparatore, B., Melloni, E. & Pontremoli, S. Protein kinase C θ is specifically localized on centrosomes and kinetochores in mitotic cells. Biochem. J. 337, 113-118 (1999).
96. Passalacqua, M. et al. Protein kinase C θ is specifically activated in murine erythroleukaemia cells during mitosis. FEBS Lett. 453, 249-253 (1999).
97. Mochly-Rosen, D., Khaner, H. & Lopez, J. Identification of intracellular receptor proteins for activated protein kinase C. Proc. Natl Acad. Sci. USA 88, 3997-4000 (1991).
98. Hyatt, S. L., Liao, L., Chapline, C. & Jaken, S. Identification and characterization of α-protein kinase C binding proteins in normal and transformed REF52 cells. Biochemistry 33, 1223-1228 (1994).
99. Kheifets, V. & Mochly-Rosen, D. Insight into intra-and inter-molecular interactions of PKC: design of specific modulators of kinase function. Pharmacol. Res. 55, 467-476 (2007).
100. Ron, D. et al. Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins. Proc. Natl Acad. Sci. USA 91, 839-843 (1994).
101. Coussens, L., Rhee, L., Parker, P. J. & Ullrich, A. Alternative splicing increases the diversity of the human protein-kinase C family. DNA 6, 389-394 (1987).
102. Adwan, T. S., Ohm, A. M., Jones, D. N. M., Humphries, M. J. & Reyland, M. E. Regulated binding of importin-α to protein kinase Cλ in response to apoptotic signals facilitates nuclear import. J. Biol. Chem. 286, 35716-35724 (2011).
103. Zinzalla, G. & Thurston, D. E. Targeting protein- protein interactions for therapeutic intervention: a challenge for the future. Future Med. Chem. 1, 65-93 (2009).
104. Souroujon, M. C. & Mochly-Rosen, D. Peptide modulators of protein-protein interactions in intracellular signaling. Nature Biotech. 16, 919-924 (1998).
105. Churchill, E. N., Qvit, N. & Mochly-Rosen, D. Rationally designed peptide regulators of protein kinase C. Trends Endocrinol. Metab. 20, 25-33 (2009).
106. Qvit, N. & Mochly-Rosen, D. Highly specific modulators of protein kinase C localization: applications to heart failure. Drug Discov. Today Dis. Mech. 7, e87-e93 (2010).
107. Prekeris, R., Mayhew, M. W., Cooper, J. B. & Terrian, D. M. Identification and localization of an actin-binding motif that is unique to the epsilon isoform of protein kinase C and participates in the regulation of synaptic function. J. Cell Biol. 132, 77-90 (1996).
108. Stebbins, E. G. & Mochly-Rosen, D. Binding specificity for RACK1 resides in the V5 region of βII protein kinase C. J. Biol. Chem. 276, 29644-29650 (2001).
109. Ferreira, J. C. et al. Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy. J. Mol. Cell. Cardiol. 51, 980-987 (2011).
110. Caino, M. C., Lopez-Haber, C., Kim, J., Mochly-Rosen, D. & Kazanietz, M. G. Protein kinase Cε is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes. Oncogene 31, 2593-2600 (2012).
111. Friedman, E., Hoau Yan, W., Levinson, D., Connell, T. A. & Singh, H. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol. Psychiatry 33, 520-525 (1993).
112. Hahn, C. G. & Friedman, E. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord. 1, 81-86 (1999).
113. Podar, K., Raab, M. S., Chauhan, D. & Anderson, K. C. The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin. Investig. Drugs 16, 1693-1707 (2007).
114. Ali, A. S., Ali, S., El Rayes, B. F., Philip, P. A. & Sarkar, F. H. Exploitation of protein kinase C: a useful target for cancer therapy. Cancer Treat. Rev. 35, 1-8 (2009).
115. Reyland, M. E. Protein kinase C isoforms: multi-functional regulators of cell life and death. Front. Biosci. 14, 2386-2399 (2009).
116. Bosco, R. et al. Fine tuning of protein kinase C (PKC) isoforms in cancer: shortening the distance from the laboratory to the bedside. Mini Rev. Med. Chem. 11, 185-199 (2011).
117. Teicher, B. A. Protein kinase C as a therapeutic target. Clin. Cancer Res. 12, 5336-5345 (2006).
118. Budas, G. R., Churchill, E. N. & Mochly-Rosen, D. Cardioprotective mechanisms of PKC isozyme-selective activators and inhibitors in the treatment of ischemia-reperfusion injury. Pharmacol. Res. 55, 523-536 (2007).
119. Pravdic, D. et al. Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C ε-mediated pathway. Anesthesiology 111, 267-274 (2009).
120. Philip, P. A. et al. Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor α induction in vivo. J. Natl Cancer Inst. 85, 1812-1818 (1993).
121. Propper, D. J. et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br. J. Cancer 78, 1337-1341 (1998).
122. Gonzalez, R., Ebbinghaus, S., Henthorn, T. K., Miller, D. & Kraft, A. S. Treatment of patients with metastatic melanoma with bryostatin 1 - a phase II study. Melanoma Res. 9, 599-606 (1999).
123. Bedikian, A. Y. et al. Phase II evaluation of bryostatin 1 in metastatic melanoma. Melanoma Res. 11, 183-188 (2001).
124. Brockstein, B. et al. Phase II studies of bryostatin 1 in patients with advanced sarcoma and advanced head and neck cancer. Invest. New Drugs 19, 249-254 (2001).
125. Varterasian, M. L. et al. Phase II study of bryostatin 1 in patients with relapsed multiple myeloma. Invest. New Drugs 19, 245-247 (2001).
126. Zonder, J. A. et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res. 7, 38-42 (2001).
127. Pfister, D. G. et al. A phase II trial of bryostatin 1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Invest. New Drugs 20, 123-127 (2002).
128. Winegarden, J. D. et al. A phase II study of bryostatin 1 and paclitaxel in patients with advanced non-small cell lung cancer. Lung Cancer 39, 191-196 (2003).
129. Nezhat, F. et al. Phase II trial of the combination of bryostatin 1 and cisplatin in advanced or recurrent carcinoma of the cervix: a New York Gynecologic Oncology Group study. Gynecol. Oncol. 93, 144-148 (2004).
130. Lam, A. P. et al. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin 1 in advanced pancreatic carcinoma. Am. J. Clin. Oncol. 33, 121-124 (2010).
131. Haas, N. B. et al. Weekly bryostatin 1 in metastatic renal cell carcinoma: a phase II study. Clin. Cancer Res. 9, 109-114 (2003).
132. Madhusudan, S. et al. A multicentre phase II trial of bryostatin 1 in patients with advanced renal cancer. Br. J. Cancer 89, 1418-1422 (2003).
133. Ajani, J. A. 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. Invest. New Drugs 24, 353-357 (2006).
134. Ku, G. Y. et al. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin 1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol. 62, 875-880 (2008).
135. Cripps, M. C. et al. Phase II randomized study of ISIS 3521 and ISIS 5132 in patients with locally advanced or metastatic colorectal cancer: a National Cancer Institute of Canada clinical trials group study. Clin. Cancer Res. 8, 2188-2192 (2002).
136. Tolcher, A. W. et al. A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 8, 2530-2535 (2002).
137. Marshall, J. L. et al. A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer. Clin. Colorectal Cancer 4, 268-274 (2004).
138. Advani, R. et al. A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C α administered as a 24 hour weekly infusion schedule in patients with advanced cancer. Invest. New Drugs 23, 467-477 (2005).
139. Rao, S. et al. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase Cα, in patients with previously treated low-grade non-Hodgkin's lymphoma. Ann. Oncol. 15, 1413-1418 (2004).
140. Lynch, T. J. et al. Randomized phase III trial of chemotherapy and antisense oligonucleotide LY9000003 (ISIS 3521) in patients with advanced NSCLC: initial report. Proc. Am. Soc. Clin. Oncol. 22, 623 (2003).
141. Paz-Ares, L. et al. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C α antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 24, 1428-1434 (2006).
142. Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory diffuse large B cell lymphoma. J. Clin. Oncol. 25, 1741-1746 (2007).
143. Morschhauser, F. et al. A phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Ann. Oncol. 19, 247-253 (2008).
144. Oh, Y. et al. Enzastaurin, an oral serine/threonine kinase inhibitor, as second-or third-line therapy of non-small-cell lung cancer. J. Clin. Oncol. 26, 1135-1141 (2008).
145. Glimelius, B. et al. A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer. Ann. Oncol. 21, 1020-1026 (2010).
146. Kreisl, T. N. et al. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol. 12, 181-189 (2010).
147. Usha, L. et al. A Gynecologic Oncology Group phase II trial of the protein kinase C β inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol. Oncol. 121, 455-461 (2011).
148. Socinski, M. A. et al. Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer. J. Thorac. Oncol. 5, 1963-1969 (2010).
149. Couldwell, W. T. et al. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Clin. Cancer Res. 2, 619-622 (1996).
150. Bergan, R. C. et al. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 5, 2366-2373 (1999).
151. Robins, H. I. et al. Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR 0021. Neuro Oncol. 8, 47-52 (2006).
152. Millward, M. J. et al. The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br. J. Cancer 95, 829-834 (2006).
153. Fischer, T. 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. J. Clin. Oncol. 28, 4339-4345 (2010).
154. Rini, B. I. et al. Time to disease progression to evaluate a novel protein kinase C inhibitor, UCN 01, in renal cell carcinoma. Cancer 101, 90-95 (2004).
155. Welch, S. et al. UCN 01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. Gynecol. Oncol. 106, 305-310 (2007).
156. Packer, M. et al. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J. Am. Coll. Cardiol. 22, 65-72 (1993).
157. DeMets, D. L. & Califf, R. M. Lessons learned from recent cardiovascular clinical trials: part II. Circulation 106, 880-886 (2002).
158. Aiello, L. P. et al. Oral protein kinase Cβ inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the protein kinase Cβ inhibitor-diabetic retinopathy study and the protein kinase Cβ inhibitor-diabetic retinopathy study 2. Retina 31, 2084-2094 (2011).
159. Ladage, D. et al. Inhibition of PKC α/β with ruboxistaurin antagonizes heart failure in pigs after myocardial infarction injury. Circ. Res. 109, 1396-1400 (2011).
160. Churchill, E. N. & Mochly-Rosen, D. The roles of PKCλ and ε isoenzymes in the regulation of myocardial ischaemia/reperfusion injury. Biochem. Soc. Trans. 35, 1040-1042 (2007).
161. Julier, K. et al. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology 98, 1315-1327 (2003).
162. Guarracino, F. et al. Myocardial damage prevented by volatile anesthetics: a multicenter randomized controlled study. J. Cardiothorac. Vasc. Anesth. 20, 477-483 (2006).
163. Lee, M. C. et al. Isoflurane preconditioning-induced cardio-protection in patients undergoing coronary artery bypass grafting. Eur. J. Anaesthesiol. 23, 841-847 (2006).
164. Tritapepe, L. et al. Cardiac protection by volatile anaesthetics: a multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Eur. J. Anaesthesiol. 24, 323-331 (2007).
165. De Hert, S. et al. A comparison of volatile and non volatile agents for cardioprotection during on pump coronary surgery. Anaesthesia 64, 953-960 (2009).
166. Mentzer, R. M. Jr. et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann. Surg. 229, 643-649; discussion 649-650 (1999).
167. Belhomme, D. et al. Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery? Ann. Thorac. Surg. 70, 590-594 (2000).
168. Jin, Z. et al. The myocardial protective effects of adenosine pretreatment in children undergoing cardiac surgery: a randomized controlled clinical trial. Eur. J. Cardiothorac. Surg. 39, e90-e96 (2011).
169. Mangano, D. T., Miao, Y., Tudor, I. C. & Dietzel, C. Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine. J. Am. Coll. Cardiol. 48, 206-214 (2006).
170. Newman, M. F. et al. Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial. JAMA 308, 157-164 (2012).
171. Ross, A. M., Gibbons, R. J., Stone, G. W., Kloner, R. A. & Alexander, R. W. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD II). J. Am. Coll. Cardiol. 45, 1775-1780 (2005).
172. Bates, E. et al. Intracoronary KAI 9803 as an adjunct to primary percutaneous coronary intervention for acute ST segment elevation myocardial infarction. Circulation 117, 886-896 (2008).
173. Lincoff, A. M. Selective inhibition of delta protein kinase C to reduce infarct size after primary percutaneous intervention for acute myocardial infarction: the PROTECTION-AMI Phase 2b clinical trial. theheart.org website [online], http://www. theheart.org/podcast/video/trials-and-pis/protectionami- with-dr-michael-lincoff.do (2011).
174. PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase Cβ Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 54, 2188-2197 (2005).
175. Aiello, L. P. et al. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy. Ophthalmology 113, 2221-2230 (2006).
176. Sheetz, M. J. et al. Effect of ruboxistaurin (RBX) on visual acuity decline over a 6 year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC DRS2). Retina 31, 1053-1059 (2011).
177. PKC-DMES Study Group. Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial. Arch. Ophthalmol. 125, 318-324 (2007).
178. Campochiaro, P. A. Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412. Invest. Ophthalmol. Vis. Sci. 45, 922-931 (2004).
179. Tuttle, K. R. et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 28, 2686-2690 (2005).
180. Tuttle, K. R., McGill, J. B., Haney, D. J., Lin, T. E. & Anderson, P. W. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin. J. Am. Soc. Nephrol. 2, 631-636 (2007).
181. Vinik, A. I. et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase Cβ-inhibitor ruboxistaurin mesylate during a 1 year, randomized, placebo-controlled, double-blind clinical trial. Clin. Ther. 27, 1164-1180 (2005).
182. Casellini, C. M. et al. A 6 month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C β inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care 30, 896-902 (2007).
183. Bebchuk, J. M. et al. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch. Gen. Psychiatry 57, 95-97 (2000).
184. Zarate, C. A. Jr. et al. Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord. 9, 561-570 (2007).
185. Yildiz, A., Guleryuz, S., Ankerst, D. P., Ongur, D. & Renshaw, P. F. Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen. Arch. Gen. Psychiatry 65, 255-263 (2008).
186. Amrollahi, Z. et al. Double-blind, randomized, placebo-controlled 6 week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J. Affect Disord. 129, 327-331 (2011).
187. Budde, K. et al. Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal-transplant recipients. Am. J. Transplant. 10, 571-581 (2010).
188. Friman, S. et al. Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. Am. J. Transplant. 11, 1444-1455 (2011).
189. Begely, C. G. & Ellis, L. M. Raise standards for preclinical cancer reseach. Nature 483, 531-533 (2012).
190. Davis, M. I. et al. Comprehensive analysis of kinase inhibitor selectivity. Nature Biotech. 29, 1046-1051 (2011).
191. Saxena, C., Zhen, E., Higgs, R. E. & Hale, J. E. An immuno-chemo-proteomics method for drug target deconvolution. J. Proteome Res. 7, 3490-3497 (2008).
192. Harper, M. T. & Poole, A. W. Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation. J. Thromb. Haemost. 8, 454-462 (2010).
193. Duquesnes, N., Lezoualc'h, F. & Crozatier, B. PKC-delta and PKC-epsilon: foes of the same family or strangers? J. Mol. Cell. Cardiol. 51, 665-673 (2011).
194. Yang, X., Cohen, M. V. & Downey, J. M. Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc. Drugs Ther. 24, 225-234 (2010).
195. Chen, C. H. et al. Activation of aldehyde dehydrogenase 2 reduces ischemic damage to the heart. Science 321, 1493-1495 (2008).
196. Ikeno, F., Inagaki, K., Rezaee, M. & Mochly-Rosen, D. Impaired perfusion after myocardial infarction is due to reperfusion-induced λPKC-mediated myocardial damage. Cardiovasc. Res. 73, 699-709 (2007).
197. Ferreira, J. C., Mochly-Rosen, D. & Boutjdir, M. Regulation of cardiac excitability by protein kinase C isozymes. Front. Biosci. 4, 532-546 (2012).
198. Inagaki, K., Koyanagi, T., Berry, N. C., Sun, L. & Mochly-Rosen, D. Pharmacological inhibition of ε-protein kinase C attenuates cardiac fibrosis and dysfunction in hypertension-induced heart failure. Hypertension 51, 1565-1569 (2008).
199. Braz, J. C. et al. PKC-α regulates cardiac contractility and propensity toward heart failure. Nature Med. 10, 248-254 (2004).
200. Braun, M. U. & Mochly-Rosen, D. Opposing effects of λ-and ζ-protein kinase C isozymes on cardiac fibroblast proliferation: use of isozyme-selective inhibitors. J. Mol. Cell. Cardiol. 35, 895-903 (2003).
201. Liu, Q. & Molkentin, J. D. Protein kinase Cα as a heart failure therapeutic target. J. Mol. Cell. Cardiol. 51, 474-478 (2011).
202. Hoyt, R. E. & Bowling, L. S. Reducing readmissions for congestive heart failure. Am. Fam. Physician 63, 1593-1598 (2001).
203. Simonis, G. et al. Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy. Mol. Cell. Biochem. 305, 103-111 (2007).
204. Bowman, J. C. et al. Expression of protein kinase Cβ in the heart causes hypertrophy in adult mice and sudden death in neonates. J. Clin. Invest. 100, 2189-2195 (1997).
205. Hambleton, M. et al. Pharmacological-and gene therapy-based inhibition of protein kinase Cα/β enhances cardiac contractility and attenuates heart failure. Circulation 114, 574-582 (2006).
206. Huang, L. et al. Increased contractility and altered Ca2+ transients of mouse heart myocytes conditionally expressing PKCβ. Am. J. Physiol. Cell Physiol. 280, C1114-C1120 (2001).
207. Roman, B. B., Geenen, D. L., Leitges, M. & Buttrick, P. M. PKC-β is not necessary for cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 280, H2264-H2270 (2001).
208. Takeishi, Y. et al. In vivo phosphorylation of cardiac troponin I by protein kinase Cβ2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J. Clin. Invest. 102, 72-78 (1998).
209. Ferreira, J. C., Boer, B. N., Grinberg, M., Brum, P. C. & Mochly-Rosen, D. Protein quality control disruption by PKCßII in heart failure; rescue by the selective PKCßII inhibitor, βIIV5 3. PLoS ONE 7, e33175 (2012).
210. Connelly, K. A. et al. Inhibition of protein kinase C β by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ. Heart Fail. 2, 129-137 (2009).
211. Ding, R. Q., Tsao, J., Chai, H., Mochly-Rosen, D. & Zhou, W. Therapeutic potential for protein kinase C inhibitor in vascular restenosis. J. Cardiovasc. Pharmacol. Ther. 16, 160-167 (2011).
212. Deuse, T. et al. Sustained inhibition of epsilon protein kinase C inhibits vascular restenosis after balloon injury and stenting. Circulation 122, S170-S178 (2010).
213. Griner, E. M. & Kazanietz, M. G. Protein kinase C and other diacylglycerol effectors in cancer. Nature Rev. Cancer 7, 281-294 (2007).
214. Blumberg, P. M., Delclos, K. B., Dunphy, W. G. & Jaken, S. Specific binding of phorbol ester tumor promoters to mouse tissues and cultured cells. Carcinog. Compr. Surv. 7, 519-535 (1982).
215. Kheifets, V., Bright, R., Inagaki, K., Schechtman, D. & Mochly-Rosen, D. Protein kinase Cλ (λPKC)-annexin V interaction: a required step in λPKC translocation and function. J. Biol. Chem. 281, 23218-23226 (2006).
216. Toker, A. et al. Multiple isoforms of a protein kinase C inhibitor (KCIP 1/14 3 3) from sheep brain - amino acid sequence of phosphorylated forms. Eur. J. Biochem. 206, 453-461 (1992).
217. Gold, M. G. et al. Architecture and dynamics of an A kinase anchoring protein 79 (AKAP79) signaling complex. Proc. Natl Acad. Sci. USA 108, 6426-6431 (2011).
218. Klauck, T. M. et al. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271, 1589-1592 (1996).
219. Chapline, C. et al. A major, transformation-sensitive PKC-binding protein is also a PKC substrate involved in cytoskeletal remodeling. J. Biol. Chem. 273, 19482-19489 (1998).
220. Mochly-Rosen, D., Khaner, H., Lopez, J. & Smith, B. L. Intracellular receptors for activated protein kinase C. Identification of a binding site for the enzyme. J. Biol. Chem. 266, 14866-14868 (1991).
221. Ron, D., Luo, J. & Mochly-Rosen, D. C2 region-derived peptides inhibit translocation and function of β protein kinase C in vivo. J. Biol. Chem. 270, 24180-24187 (1995).
222. House, C. & Kemp, B. E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science 238, 1726-1728 (1987).
223. Ron, D. & Mochly-Rosen, D. An autoregulatory region in protein kinase C: the pseudoanchoring site. Proc. Natl Acad. Sci. USA 92, 492-496 (1995).
224. Dorn, G. W. et al. Sustained in vivo cardiac protection by a rationally designed peptide that causes ε protein kinase C translocation. Proc. Natl Acad. Sci. USA 96, 12798-12803 (1999).
225. Inagaki, K. et al. Inhibition of λ-protein kinase C protects against reperfusion injury of the ischemic heart in vivo. Circulation 108, 2304-2307 (2003).
226. Armstrong, J. S. & Whiteman, M. Measurement of reactive oxygen species in cells and mitochondria. Methods Cell Biol. 80, 355-377 (2007).
227. Murriel, C. L., Churchill, E., Inagaki, K., Szweda, L. I. & Mochly-Rosen, D. Protein kinase Cλ activation induces apoptosis in response to cardiac ischemia and reperfusion damage: a mechanism involving BAD and the mitochondria. J. Biol. Chem. 279, 47985-47991 (2004).
228. Konopatskaya, O. & Poole, A. W. Protein kinase Cα: disease regulator and therapeutic target. Trends Pharmacol. Sci. 31, 8-14 (2010).
229. Gorin, M. A. & Pan, Q. Protein kinase Cε: an oncogene and emerging tumor biomarker. Mol. Cancer 8, 9 (2009).
230. Lee, S. K. et al. Apurinic/apyrimidinic endonuclease 1 inhibits protein kinase C mediated p66shc phosphorylation and vasoconstriction. Cardiovasc. Res. 91, 502-509 (2011).
231. Standaert, M. L. et al. Effects of knockout of the protein kinase Cβ gene on glucose transport and glucose homeostasis. Endocrinology 140, 4470-4477 (1999).
232. Chen, C. & Mochly-Rosen, D. Opposing effects of λ and εPKC in ethanol-induced cardioprotection. J. Mol. Cell. Cardiol. 33, 581-585 (2001).
233. Mochly-Rosen, D. et al. Cardiotrophic effects of protein kinase Cε: analysis by in vivo modulation of PKCε translocation. Circ. Res. 86, 1173-1179 (2000).
234. Koide, Y. et al. Differential induction of protein kinase C isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats. Hypertens. Res. 26, 421-426 (2003).
235. Limnander, A. et al. STIM1, PKC-λ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature Immunol. 12, 425-433 (2011).
236. Kilpatrick, L. E. et al. Protection against sepsis-induced lung injury by selective inhibition of protein kinase C λ (λ-PKC). J. Leukoc. Biol. 89, 3-10 (2011).
237. Boschelli, D. H. Small molecule inhibitors of PKCθ as potential antiinflammatory therapeutics. Curr. Top. Med. Chem. 9, 640-654 (2009).
238. Bright, R., Steinberg, G. K. & Mochly-Rosen, D. λPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo. Brain Res. 1144, 146-155 (2007).
239. Chou, W. H. & Messing, R. O. Hypertensive encephalopathy and the blood-brain barrier: is λPKC a gatekeeper? J. Clin. Invest. 118, 17-20 (2008).
240. Qi, X., Disatnik, M. H., Shen, N., Sobel, R. A. & Mochly-Rosen, D. Aberrant mitochondrial fission in neurons induced by protein kinase Cλ under oxidative stress conditions in vivo. Mol. Biol. Cell 22, 256-265 (2011).
241. Bright, R., Sun, G. H., Yenari, M. A., Steinberg, G. K. & Mochly-Rosen, D. εPKC confers acute tolerance to cerebral ischemic reperfusion injury. Neurosci. Lett. 441, 120-124 (2008).
242. Langlois, A. et al. Crucial implication of protein kinase C (PKC)-λ, PKC-ζ, ERK 1/2, and p38 MAPK in migration of human asthmatic eosinophils. J. Leukoc. Biol. 85, 656-663 (2009).
243. Kanthasamy, A. G. et al. A novel peptide inhibitor targeted to caspase 3 cleavage site of a proapoptotic kinase protein kinase Cλ (PKCλ) protects against dopaminergic neuronal degeneration in Parkinson's disease models. Free Radic. Biol. Med. 41, 1578-1589 (2006).
244. Sawada, M., Imamura, K. & Nagatsu, T. Role of cytokines in inflammatory process in Parkinson's disease. J. Neural Transm. Suppl. 2006, 373-381 (2006).
245. Defauw, J. M. et al. Synthesis and protein kinase C inhibitory activities of acyclic balanol analogs that are highly selective for protein kinase C over protein kinase A. J. Med. Chem. 39, 5215-5227 (1996).
246. Swannie, H. C. & Kaye, S. B. Protein kinase C inhibitors. Curr. Oncol. Rep. 4, 37-46 (2002).
247. Lee, K. W. et al. Enzastaurin, a protein kinase Cβ inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer. Cancer Res. 68, 1916-1926 (2008).
248. Gray, M. O., Karliner, J. S. & Mochly-Rosen, D. A selective ε-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J. Biol. Chem. 272, 30945-30951 (1997).
249. Lahn, M., Sundell, K. & Moore, S. Targeting protein kinase C α (PKC-α) in cancer with the phosphorothioate antisense oligonucleotide aprinocarsen. Ann. NY Acad. Sci. 1002, 263-270 (2003).
250. Goekjian, P. G. & Jirousek, M. R. Protein kinase C inhibitors as novel anticancer drugs. Expert Opin. Investig. Drugs 10, 2117-2140 (2001).
251. Tamaoki, T. Use and specificity of staurosporine, UCN 01, and calphostin C as protein kinase inhibitors. Methods Enzymol. 201, 340-347 (1991).
252. Kraft, A. S., Smith, J. B. & Berkow, R. L. Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL 60. Proc. Natl Acad. Sci. USA 83, 1334-1338 (1986).
253. Schwarze, S. R., Ho, A., Vocero-Akbani, A. & Dowdy, S. F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569-1572 (1999).
254. Qi, X., Inagaki, K., Sobel, R. A. & Mochly-Rosen, D. Sustained pharmacological inhibition of λPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats. J. Clin. Invest. 118, 173-182 (2008).
255. Kim, J., Thorne, S. H., Sun, L., Huang, B. & Mochly-Rosen, D. Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene 30, 323-333 (2011).
256. Inagaki, K., Begley, R., Ikeno, F. & Mochly-Rosen, D. Cardioprotection by ε-protein kinase C activation from ischemia: continuous delivery and antiarrhythmic effect of an ε-protein kinase C activating peptide. Circulation 111, 44-50 (2005).
257. Drew, B. G. & Kingwell, B. A. Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin. Pharmacother. 9, 2137-2144 (2008).
258. Zhao, B. et al. Structural basis for Chk1 inhibition by UCN 01. J. Biol. Chem. 277, 46609-46615 (2002).