+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The Novel PKC θ from Benchtop to Clinic


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          The protein kinases C (PKCs) are a family of serine/threonine kinases involved in regulating multiple essential cellular processes such as survival, proliferation, and differentiation. Of particular interest is the novel, calcium-independent PKC θ which plays a central role in immune responses. PKC θ shares structural similarities with other PKC family members, mainly consisting of an N-terminal regulatory domain and a C-terminal catalytic domain tethered by a hinge region. This isozyme, however, is unique in that it translocates to the immunological synapse between a T cell and an antigen-presenting cell (APC) upon T cell receptor-peptide MHC recognition. Thereafter, PKC θ interacts physically and functionally with downstream effectors to mediate T cell activation and differentiation, subsequently leading to inflammation. PKC θ-specific perturbations have been identified in several diseases, most notably autoimmune disorders, and hence the modulation of its activity presents an attractive therapeutic intervention. To that end, many inhibitors of PKCs and PKC θ have been developed and tested in preclinical and clinical studies. And although selectivity remains a challenge, results are promising for the future development of effective PKC θ inhibitors that would greatly advance the treatment of several T-cell mediated diseases.

          Related collections

          Most cited references225

          • Record: found
          • Abstract: found
          • Article: not found

          The protein kinase complement of the human genome.

          G. Manning (2002)
          We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
            • Record: found
            • Abstract: found
            • Article: not found

            Regulation of protein kinases; controlling activity through activation segment conformation.

            There are currently at least forty-six unique protein kinase crystal structures, twenty-four of which are available in an active state. Here we examine these structures using a structural bioinformatics approach to understand how the conformation of the activation segment controls kinase activity. Copyright 2004 Cell Press
              • Record: found
              • Abstract: found
              • Article: not found

              Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.

              The crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase complexed with a 20-amino acid substrate analog inhibitor has been solved and partially refined at 2.7 A resolution to an R factor of 0.212. The magnesium adenosine triphosphate (MgATP) binding site was located by difference Fourier synthesis. The enzyme structure is bilobal with a deep cleft between the lobes. The cleft is filled by MgATP and a portion of the inhibitor peptide. The smaller lobe, consisting mostly of amino-terminal sequence, is associated with nucleotide binding, and its largely antiparallel beta sheet architecture constitutes an unusual nucleotide binding motif. The larger lobe is dominated by helical structure with a single beta sheet at the domain interface. This lobe is primarily involved in peptide binding and catalysis. Residues 40 through 280 constitute a conserved catalytic core that is shared by more than 100 protein kinases. Most of the invariant amino acids in this conserved catalytic core are clustered at the sites of nucleotide binding and catalysis.

                Author and article information

                J Immunol Res
                J Immunol Res
                Journal of Immunology Research
                Hindawi Publishing Corporation
                19 May 2015
                : 2015
                : 348798
                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
                Author notes

                Academic Editor: Douglas C. Hooper

                Author information
                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.

                : 1 August 2014
                : 12 January 2015
                Review Article


                Comment on this article