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Regulation of Growth of Airway Smooth Muscle by Second Messenger Systems
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
The role of DAG formation in mediating mitogenesis has been supported by studies in 3T3 cells66–68 and hematopoietic cell lines69 stimulated with permeable DAG analogues. Other investigators, using 3T3 cells transfected with vectors that express the entire Ha-ras oncogene p21 protein or infected with Kirsten sarcoma virus, have observed that these cells underwent cellular transformation and have sustained increases in DAG, PC, and phosphatidylethanolamine, but unchanged PI levels.70 Increases in DAG levels with agonist stimulation may result not only from newly synthesized DAG, but also from decreased degradation. Diacylglycerol kinase (DGK), which rapidly converts DAG to phosphatidic acid, plays a central role in the degradation of DAG.71–73 To date, studies have only characterized the regulatory role of this pathway in cells undergoing malignant transformation.74 Alteration in the activity of this kinase may also affect PKC activation and, potentially, cell growth.
Pharmacological Control of Eosinophil Activation and Secretion
Published in Gerald J. Gleich, A. Barry Kay, Eosinophils in Allergy and Inflammation, 2019
Peter J. Barnes, Mark A. Giembycz
PI hydrolysis also leads to the formation of 1,2-diacylglycerol, which activates PKC (56). PKC activation with phorbol esters results in release of O2− (11,38), suggesting that PKC is involved in the activation of NADPH-dependent respiratory burst oxidase. The PKC inhibitors Ro 31-8220, which acts at the ATP-binding site, and AMG-C16, which blocks the diglyceride-binding site, both inhibit LTB4 and PAF-induced O2− generation (57) and are potentiated by the diacylglycerol kinase inhibitor R 59022 (58).
Phosphoinositide Metabolism
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
An important primary product of phosphodiesteric cleavage of phosphoinositides breakdown is 1,2-diacylglycerol, which functions as a second messenger in the regulation of cellular proliferation. Diacylglycerol is also produced through other pathways, including neosynthesis from a glycolytic intermediate, dihydroxyacetone phosphate and production from phosphatidylcholine turnover, as well as its synthesis from monoacylglycerol.78 Diacylglycerol is generated from glycerol 3-phosphate through a pathway involving step-wise acylation to lysophosphatidic acid and phosphatidic acid. Diacylglycerol is an endogenous activator of protein kinase C, and its concentration is increased by the action of a wide diversity of hormones and growth factors. Attenuation of diacylglycerol is carried out by phosphorylation by diacylglycerol kinase or degradation by diacylglycerol lipase. Diacylglycerol kinase is a ubiquitous enzyme involved in diacylglycerol remotion by its phosphorylation to phosphatidic acid. Phorbol esters may cause a redistribution of diacylglycerol kinase from the cytosol to the plasma membrane.79 The phorbol ester-induced translocation of diacylglycerol kinase is relatively small in cells transformed by acute retroviruses carrying the v-erb-B or v-src oncogenes, which may contribute to altered cellular proliferation.80
Clinical features of children with anti-CFH autoantibody-associated hemolytic uremic syndrome: a report of 8 cases
Published in Renal Failure, 2022
Qian Li, Xinxin Kong, Minle Tian, Jing Wang, Zhenle Yang, Lichun Yu, Suwen Liu, Cong Wang, Xiaoyuan Wang, Shuzhen Sun
Anti-CFH Ab-associated aHUS predominantly presents in childhood [9]. In this study, the age of onset of children with anti-CFH Ab-associated HUS was 5.83–13.5 years (median 6.67 years, 6.02–9.03 years). Brocklebank et al. reported that the median age at presentation was 8 years (N = 17, range, 1 ∼ 15 years) in their anti-CFH Ab-associated aHUS patient population [10]. The average age is significantly higher in anti-CFH Ab-associated HUS than in other types of HUS. Loirat et al. reported that the onset age of children with Streptococcus pneumoniae–HUS (SP-HUS) is less than 2 years old, 70% of children with Shiga toxin-producing Escherichia coli-HUS (STEC-HUS) have an onset age of less than 3 years old, and 50% of children with cobalamin C deficiency-related HUS (CblC-HUS) have an onset age of less than 0.1 years old. The onset age of HUS children with CFH and CFI mutations is mainly 2 years old and under. Children with diacylglycerol kinase ε-HUS (DGKE-HUS) have an onset age of less than 1 year old [4,11]. Regarding the sex distribution, previous articles showed that children with anti-CFH Ab-associated HUS equally effects males and females in childhood [5]. In this study, the male:female ratio was 1.67:1, and male predominance was observed, similar to the 11:6 ratio (N = 17) in the report by Brocklebank et al. [10]. More research is needed to explore the sex distribution.
Temperature signaling underlying thermotaxis and cold tolerance in Caenorhabditis elegans
Published in Journal of Neurogenetics, 2020
Asuka Takeishi, Natsune Takagaki, Atsushi Kuhara
A detailed analysis reveals that AFD T* changes happen faster than thermotaxis temperature preference changes when worms are exposed to new temperature (Biron et al., 2006; Hawk et al., 2018). AIY also shows a slower T* shift compared to AFD (Biron et al., 2006; Hawk et al., 2018). This divergence of adaptation timescale is mediated by the synaptic communication between AFD and AIY via PKC-1/TTX-4 and diacylglycerol kinase, DGK-3 (Biron et al., 2006; Hawk et al., 2018; Luo et al., 2014; Okochi, Kimura, Ohta, & Mori, 2005). Tc-independent positive thermotaxis and negative thermotaxis was observed in the pkc-1/ttx-4 mutant and in worms that overexpress constitutive-active PKC-1 into AFD (AFD::caPKC-1), respectively (Table 1) (Hawk et al., 2018; Okochi et al., 2005). The temperature response of AIY was altered in pkc-1 mutants and AFD::caPKC-1, although the AFD response was the same as wild type indicating presynaptic plasticity of the AFD–AIY synapse modulates thermotaxis orientation (Hawk et al., 2018). Worms also exhibit constitutive positive thermotaxis when ectopic gap junctions are overexpressed in AFD and AIY (Table 1) (Hawk et al., 2018). These results suggest communication of AIY and AFD is important in determining the temperature preference (Hawk et al., 2018; Narayan, Laurent, & Sternberg, 2011).
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.