Journal of Immunology Research
Volume 2015 (2015), Article ID 348798, 16 pages
http://dx.doi.org/10.1155/2015/348798
The Novel PKCθ from Benchtop to Clinic
1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Infectious Diseases, and Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, P.O. Box 11-0236, Riad El Solh, Beirut, Lebanon
2Department of Biomedical Science, Faculty of Health Sciences, Global University, P.O. Box 15-5085, Batrakiyye, Beirut, Lebanon
3Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, P.O. Box 11-0236, Riad El Solh, Beirut, Lebanon
Received 1 August 2014; Accepted 12 January 2015
Academic Editor: Douglas C. Hooper
Copyright © 2015 Rouba Hage-Sleiman et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Linked References
- A. C. Newton, “Protein kinase C: structure, function, and regulation,” Journal of Biological Chemistry, vol. 270, no. 48, pp. 28495–28498, 1995. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- H. Mellor and P. J. Parker, “The extended protein kinase C superfamily,” Biochemical Journal, vol. 332, part 2, pp. 281–292, 1998. View at Google Scholar · View at Scopus
- Y. Nishizuka, “Protein kinase C and lipid signaling for sustained cellular responses,” The FASEB Journal, vol. 9, no. 7, pp. 484–496, 1995. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- S. S. Taylor and E. Radzio-Andzelm, “Three protein kinase structures define a common motif,” Structure, vol. 2, no. 5, pp. 345–355, 1994. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- E. M. Dutil and A. C. Newton, “Dual role of pseudosubstrate in the coordinated regulation of protein kinase C by phosphorylation and diacylglycerol,” TheJournal of Biological Chemistry, vol. 275, no. 14, pp. 10697–10701, 2000. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- E. M. Dutil, L. M. Keranen, A. A. DePaoli-Roach, and A. C. Newton, “In vivo regulation of protein kinase C by trans-phosphorylation followed by autophosphorylation,” The Journal of Biological Chemistry, vol. 269, no. 47, pp. 29359–29362, 1994. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- E. Sontag, J.-M. Sontag, and A. Garcia, “Protein phosphatase 2A is a critical regulator of protein kinase C 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- D. Schechtman and D. Mochly-Rosen, “Adaptor proteins in protein kinase C-mediated signal transduction,” Oncogene, vol. 20, no. 44, pp. 6339–6347, 2001. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- N. Isakov and A. Altman, “PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors,” Frontiers in Immunology, vol. 3, article 273, 2012. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- J. L. Cannons, L. J. Yu, B. Hill et al., “SAP regulates TH2 differentiation and PKC-θ-mediated activation of NF-κB1,” Immunity, vol. 21, no. 5, pp. 693–706, 2004. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- N. Thuille, C. Lutz-Nicoladoni, T. Letschka, N. Hermann-Kleiter, I. Heit, and G. Baier, “PKCtheta and Itk functionally interact during primary mouse CD3+ T cell activation,” Immunology Letters, vol. 126, no. 1-2, pp. 54–59, 2009. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar
- T. Letschka, V. Kollmann, C. Pfeifhofer-Obermair et al., “PKC-theta selectively controls the adhesion-stimulating molecule Rap1,” Blood, vol. 112, no. 12, pp. 4617–4627, 2008. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- M. Huse, “Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond,” Frontiers in Immunology, vol. 3, p. 235, 2012. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- C. Pfeifhofer, K. Kofler, T. Gruber et al., “Protein kinase C theta affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells,” Journal of Experimental Medicine, vol. 197, no. 11, pp. 1525–1535, 2003. View at Publisher · View at Google Scholar · View at Scopus
- A. Altman, S. Kaminski, V. Busuttil et al., “Positive feedback regulation of PLCγ1/Ca2+ 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- S. Sakaguchi, T. Yamaguchi, T. Nomura, and M. Ono, “Regulatory T cells and immune tolerance,” Cell, vol. 133, no. 5, pp. 775–787, 2008. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- Z. Sun, “Intervention of PKC-θ as an immunosuppressive regimen,” Frontiers in Immunology, vol. 3, p. 225, 2012. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- L. Madaro, V. Marrocco, S. Carnio, M. Sandri, and M. Bouché, “Intracellular signaling in ER stress-induced autophagy in skeletal muscle cells,” The FASEB Journal, vol. 27, no. 5, pp. 1990–2000, 2013. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- S. Ghosh, A. Adhikary, S. Chakraborty et al., “Nifetepimine, a dihydropyrimidone, ensures CD4+ T cell survival in a tumor microenvironment by maneuvering sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA),” The Journal of Biological Chemistry, vol. 287, no. 39, pp. 32881–32896, 2012. View at Publisher · View at Google Scholar · View at Scopus
- J. Garaude, S. Kaminski, S. Charni et al., “Impaired anti-leukemic immune response in PKCtheta-deficient mice,” Molecular Immunology, vol. 45, no. 12, pp. 3463–3469, 2008. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- H. C. Swannie and S. B. Kaye, “Protein kinase C inhibitors,” Current Oncology Reports, vol. 4, no. 1, pp. 37–46, 2002. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Google Scholar
- 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. View at Publisher · View at Google Scholar
- 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. View at Publisher · View at Google Scholar
- L. Nathan Tumey, D. H. Boschelli, J. Lee, and D. Chaudhary, “2-Alkenylthieno[2,3-b]pyridine-5-carbonitriles: potent and selective inhibitors of PKCθ,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 15, pp. 4420–4423, 2008. View at Publisher · View at Google Scholar · View at Scopus
- 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. View at Publisher · View at Google Scholar · View at Scopus