Regulation of Immune System Cell Functions by Protein Kinase C


Cellular responses to environmental cues are mediated through complex networks of signal transduction pathways. Among the molecules involved in these pathways, members of the protein kinase C (PKC) family stand out because of their ability to acutely and reversibly modulate effector protein functions and control the spatial distribution and dynamic properties of the signals. PKC enzymes also contribute to signaling networks that coordinate many aspects of immune cell function and, therefore, are important players in immune regulation. Originally discovered in 1977, by Nishizuka and coworkers, PKC was initially identified as a cyclic nucleotide-independent protein kinase that is capable of phosphorylating histone and protamine following Ca2+-dependent limited proteolysis of its proenzyme precursor (1, 2). Subsequently, Nishizuka demonstrated that activation of PKC can occur in the absence of limited proteolysis by a membrane-associated factor and low Ca2+ concentration (3). He then characterized the membrane-associated factor as diacylglycerol, which is generated by receptor-stimulated hydrolysis of phosphoinositides, suggesting that this lipid functions as a second messenger (4). These findings and additional data established a new pathway of signal transduction and led to identification of biological roles for PKC in signaling pathways linked to a variety of surface receptors in many different cell types. The PKC family of serine/threonine kinases consists of 10 distinct isoforms that are differentially expressed in a wide range of cell types and tissues. Despite having a certain degree of redundancy and overlapping substrate specificities, individual PKC isoforms also exhibit non-redundant functions. In addition, activity of distinct isoforms can be deployed in a spatially and temporally dependent manner since most isoforms possess a structurally and differentially activated unique regulatory domain. The activity of PKC can therefore be induced by a large variety of agonists and directed by multiple inputs, including second messengers and a variety of PKC-binding proteins. This Research Topic focuses on recent developments relevant to the role of PKC in immune cell functions, and includes contributions by many of the leading experts in the field. The first paper by Pfeifhofer-Obermair and colleagues (5) reviews current information related to the physiological role and nonredundant functions of different PKC isoforms in T lymphocytes. The authors emphasize the positive contributions of PKCθ (6) and PKCα (7) to antigen-induced T cell activation and argue that inhibition T cell-mediated responses, including allograft rejection and autoimmunity, requires the inhibition of both PKC isoforms. Black and Black (8) discuss mechanisms of regulation of T cell proliferation and cell cycle progression that are mediated by distinct PKC isoforms and emphasize their predominant role during the G0/G1 and G2 phases. Although PKC was found to modulate an array of cell cycle regulatory molecules, evidence points to Cdk kinase inhibitors and D-type cyclins as the key mediators of PKCregulated cell cycle-specific effects. The authors indicate that most PKC isoforms play positive roles during cell cycle progression, except for PKCδ, which serves as a negative regulator. Another important cellular function that involves PKC is the establishment and maintenance of cell polarity. This mechanism enables, among other things, the formation of a functional immunological synapse (IS) at the T cell-antigen presenting cell (APC) contact area, and the directional release of cytokines and cytolytic factors from cytotoxic T cells toward their specific target cells. The microtubule organizing complex (MTOC) plays an important role in directing this polarity, and the review by M. Huse covers the process through which PKC family members regulate the formation of the MTOC and its link to the T cell IS (9). The PKCθ isoform, which is selectively enriched in T cells (10), is a key modulator of T cell receptor (TCR) signaling and an essential regulator of T cell activation and survival (11). In antigen-stimulated T cells, PKCθ selectively translocates to the center of the IS, where it mediates critical TCR and CD28 signals leading to the activation of NF-κB, AP-1 and NFAT transcription factors (12). A review by Wang and coworkers (13) discusses a major mechanism that regulates PKCθ, and is also shared by other kinases. This mechanism involves a post-translational process whereby distinct serine, threonine, and tyrosine residues of PKCθ are autophosphorylated or transphosphorylated, thereby regulating its catalytic activity, as well as its localization within cells and the ability to interact with specific binding partners. The authors focus on the actual PKCθ phosphorylation sites and their potential role in determining PKCθ functions. A short comment on this topic is presented by Freeley and Long (14). Another manuscript, by Isakov and Altman (15), focuses on the molecular mechanism that regulates the translocation of PKCθ to

DOI: 10.3389/fimmu.2013.00384

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@inproceedings{Isakov2013RegulationOI, title={Regulation of Immune System Cell Functions by Protein Kinase C}, author={Noah Isakov and Amnon Altman}, booktitle={Front. Immunol.}, year={2013} }