Phosphoinositide Metabolism
Enrique Pimentel in Handbook of Growth Factors, 2017
Phosphorylation of protein kinase C may contribute to regulate its activity. The enzyme can undergo autophosphorylation at multiple sites,215 and the resulting autophosphorylated kinase has a lower Ka for Ca2+ and a higher affinity for phorbol ester than the nonphosphorylated enzyme, but still requires Ca2+ and phospholipid for maximal activity. Compounds that interact with the catalytic site of protein kinase C, competing with ATP, act as inhibitors of the enzyme in a concentration-dependent manner.216 Casein kinase I, but not casein kinase II, can phosphorylate protein kinase C in the absence of Ca2+ and phospholipids.217 The possible role of autophosphorylation or trans-phosphorylation in the regulation of protein kinase activity in intact cells is not understood.
Apoptosis: Cellular Signaling and Molecular Mechanisms
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
Alteration of intracellular Ca2+ concentration is not the only signal which can induce apoptosis. Indeed, Ca2+ is actually able to protect sympathetic nerve ganglion cells and pre-B cells (BAF-3) from apoptosis following removal of nerve growth factor and IL-3, respectively.38,39 In addition, apoptosis in thymocytes is inhibited if protein kinase C is activated by phorbol esters concurrently with an increase in intracellular Ca2+ concentration.2 Treatment of immature thymocytes with the T cell mitogen concanavalin A (Con A) causes activation of protein kinase C and an increase in intracellular Ca2+, ultimately leading to proliferation rather than programmed cell death.37 Apoptosis proceeds, however, if these cells are exposed to Con A in the presence of protein kinase C inhibitors. Clearly, activation of protein kinase C is able to inhibit apoptosis which would normally occur after an increase in intracellular Ca2+ levels. Indeed, protein kinase C activity blocks DNA degradation induced by Ca2+ in isolated thymocyte nuclei. Thus, some of the substrates upon which this kinase acts and which regulate apoptosis must be located in the nucleus.37 These data demonstrate that protein kinase C must act as a cellular signal that leads to proliferation in some instances and apoptosis in others. Additional studies are required to identify the substrates upon which protein kinase C acts in the apoptotic pathway in different cells.
Alcohol's Promotion of Gastrointestinal Carcinogenesis
Victor R. Preedy, Ronald R. Watson in Alcohol and the Gastrointestinal Tract, 2017
Growth factors play a critical role in cell growth and invasion and a number of growth factors are reported to be synthesized or overexpressed in cancerous cells. Two of the most studied are the epidermal growth factor (EGF) and the transforming growth factor-α (TGF-α) that exhibits structural homology to EGF. Both polypeptides share a common membrane receptor.75 Of interest is the recent report of Tarnawski et al.76 that adaptation of gastric mucosa to chronic elhanol consumption was associated with increased cell proliferation along with increased expression of mucosal EGF, TGF-α, and their common receptors. Similarly, the role of protein kinases and the secondary messengers such as cAMP that are involved in regulating a diverse variety of cell functions needs to be elucidated in ethanol-induced tumor promotion. Protein kinase C (PKC) is actively involved in cell proliferation and differentiation through phosphorylation. Phorbol ester tumor promoters and related compounds bind to and activate PKC while inhibitors of PKC act as antipromoters (for a review see reference 77). Of interest is the association of altered intracellular cAMP turnover with alcoholism in humans. Abstinent alcoholics have reduced cAMP accumulation compared with normal subjects.78 Furthermore, ethanol depresses human platelet cAMP levels, which is overcome by an inhibitor of PKC, suggesting that ethanol may be acting through activation of PKC.79
Targeting oxidative stress through antioxidants in diabetes mellitus
Published in Journal of Drug Targeting, 2018
Parul Thakur, Ashwini Kumar, Awanish Kumar
Protein kinase C (PKC) is an enzyme that modulates the functions of other proteins through their phosphorylation. PKC is activated by the elevated level of DAG, derived from enhanced formation of triose phosphate via hyperglycaemia [16]. Persistent and excessive activation of several PKC isoforms operates as a third common pathway mediating tissue injury induced by diabetes-induced ROS. These results primarily from enhanced de novo synthesis of DAG from glucose via triose phosphate, whose availability is increased because increased ROS inhibit activity of the glycolytic enzyme GAPDH raising intracellular levels of the DAG precursor triose phosphate. Enhanced PKC activity induces several cytokines and protein signals including plasminogen activator inhibitor (PAI-1), NF-κB, NAD(P)H oxidases, endothelin-1, transforming growth factor β (TGF-β) and extracellular matrix (ECM). These pathological alterations have been implicated in basement membrane thickening, vasoconstriction, altered capillary permeability, hypoxia and activation of angiogenesis [17,18].
Protein kinase C-θ knockout decreases serum IL-10 levels and inhibits insulin secretion from islet β cells
Published in Islets, 2021
Feng Hong, Yang Yang, Baiyi Chen, Peng Li, Guoguang Wang, Yuxin Jiang
As a member of the serine/threonine protein kinase family, protein kinase C (PKC) is represented by more than 10 different functional isozymes.1 Based on the structural differences, PKC can be classified into several categories: 1) classical, including α, β, and γ members; 2) novel, including δ, ε, and η; 3) atypical, including ζ and ι; and 4) PKC-related kinases (PRKs).2 PKCs participate in many biological processes including cell proliferation, differentiation, and apoptosis.3 Several PKC isoforms, such as PKC-α and PKC-ε, are present in the β cells of the pancreatic islets.4 Glucose stimulates PKC-α synthesis and promotes its translocation from the cytosol to the membrane.5,6 Inhibitors of both PKC-α and PKC-ε can decrease glucose-induced insulin secretion.7,8 PKC-δ is also expressed in pancreatic islet β cells and is essential for pancreatic β cell replication during insulin resistance.9
A novel compound heterozygous mutation in DGKE in a Chinese patient causes atypical hemolytic uremic syndrome
Published in Hematology, 2020
Jitong Li, Yinsen Song, Yaodong Zhang, Hongjiang Li, Ming Tian, Di Li, Shufeng Zhang, Guanghai Cao, Cuihua Liu
DGKE protein model predictions were performed by using the Phyre2 online tool. The C1 domain was modeled based on the c2e73A (the phorbol esters/diacylglycerol binding domain of protein kinase C gamma) template with a confidence score of 98.39, identity of 26% and coverage residues of aa 55-117 (10%) of the DGKE amino acid sequence. The integrated DAGKc, DAGKa and LC domains were modeled based on the c2qv7A (diacylglycerol kinase DgkB in complex with ADP and Mg) template with a confidence score of 100, identity of 18% and coverage residues aa 213-563 (61%) of the DGKE amino acid sequence. The 3D models were visualized with PyMOL software. The position of the residue that is altered as a result of the M1 mutation (p.C77W) is marked in pink, and the position of the residues that are altered as a consequence of the M2 mutation (p.C264Yfs*27) is marked in light green. The C1 (58-108 aa), DAGKc (219-350 aa), DAGKa (369-524 aa) and LC (548-563 aa) domains are colored blue, purple, orange and red, respectively, and the other resides of the indicated models are marked in black.
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