Hormones as Immune Modulating Agents
Thomas F. Kresina in Immune Modulating Agents, 2020
Receptor cross-linking (dimerization or oligomerization) by a single hormone molecule is required for signal transduction by the growth hormone receptor. Because of this requirement, at high hormone concentrations when each receptor is occupied by a single hormone molecule, cross-linking becomes impossible and therefore the hormone serves as its own antagonist (Figure 1) [45]. The signaling pathway for PRL and related hormones is not fully resolved. G proteins, thyrosine kinase, and protein kinase C have all been suggested to play a role [39,46,47]. Direct nuclear signaling by PRL and GH has also been proposed [48–50]. Recent information suggests that phosphorylation of transcription factors by protein kinases plays a major role in signal transduction. Deoxyribonucleic acid (DNA) binding and trans-activation can be effected both positively and negatively by these factors. Commonly GLH and cytokines use signal transducer and activator of transcription (STAT) family factors in the early phase of induction. The use of other signaling systems, such as Src-family kinases, phospholipase C/protein kinase C, and mitogen-activated protein (MAP) kinase, is variable. Although initially there are shared protein kinases and STATs, the combination of transacting factors working at a particular promoter in a given cell type is distinct, specifying a very different biological effect on hormonal stimulation. Thus, specificity of hormone action depends to a large extent on the target cells’ repertoire of transacting factors [51].
Scavenger Receptors and Lipopolysaccharide
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
Amino acid sequence of domain IV predicts that α-helical coiled-coil structure mediates the assembly of functionally active trimeric scavenger receptor via interaction of the interhelical hydrophobic residues. Point mutagenesis studies provided the evidence that domain IV is essential for dissociation of the ligands from scavenger receptor induced in lysosomes by conformational changes at low pH (28). Recent experimental evidence indicates that the α-helical coiled-coil domain also mediates a cation-independent adhesion of macrophages (29). The N-terminal cytoplasmic domain is believed to be essential for endocytosis and recycling of scavenger receptors (30). The amino acid structure of the cytoplasmic domain also suggested the potential substrate sites for protein kinase activity.
Overview of Mechanisms for Coupling of Receptor-Agonist Interactions With Physiological Effects
John C. Matthews in Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
Many membrane-associated receptor systems initiate their physiological effects through cyclic nucleotide-stimulated protein kinases or through direct stimulation of protein kinases without the requirement for the cyclic nucleotide intermediates. The best understood of these are the adenylate cyclase systems. Adenylate cyclase is an enzyme associated with the inner surface of the plasma membrane of many cells. Adenylate cyclase converts ATP to cyclic AMP. Cyclic AMP interacts with its receptor, a protein kinase enzyme, to activate it. The protein kinase then catalyzes the transfer of a phosphate group from ATP to a hydroxyl group of another enzyme or protein, to activate or inactivate that protein. The protein, which becomes phosphorylated by the action of the protein kinase, is invariably an important component of the physiological process being regulated. Its phosphorylation can either turn on or turn off (or, more likely, speed up or slow down) that entire physiological process.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
It is well known that ATP is the primary carrier of energy in cells. Upon hydrolysis, it releases energy from the chemical bonds to fuel cellular processes. For example, ATP hydrolysis by motor proteins or DNA helicases can induce conformational changes and thus drive the translocation of these proteins. In addition, the protein kinases regulate various biological processes by transferring a phosphate group from ATP to amino acid residues like serine, threonine, or tyrosine. Interestingly, the mitotic kinases Aurora B, Haspin, and Bub132 also possess intrinsic ATPase activity, producing free inorganic phosphate. It is currently unknown whether this energy-consuming activity has a physiological role in cells, further studies are needed to address this potentially interesting question.
Spider toxins targeting ligand-gated ion channels
Published in Toxin Reviews, 2021
Olena Filchakova
Purinergic receptors are activated by nucleotides and constitute LGIC (P2X) (Valera et al. 1994) and metabotropic (P2Y) receptors (Webb et al. 1993). P2X receptors are nonselective cation channels activated endogenously by ATP, and permeable to sodium and calcium (Egan and Khakh 2004). The activation of the channels leads to the membrane depolarization (Erb et al. 2006). There are seven cloned human subunits: P2X1-7. Each subunit consists of intracellular N- and C-termini, two transmembrane domains (TM1 and TM2), and large extracellular domain (Habermacher et al. 2016, North 2016) (Figure 5). The intracellular domains contain consensus phosphorylation sites for protein kinases and were shown to be modulated by protein kinases PKA and PKC (Boue-Grabot et al. 2000, Brown and Yule 2010). The TM1 domain gates the channel while TM2 lines the channel pore. The extracellular domain contains orthosteric ATP-binding site as well as a site that permits allosteric modulation of the receptor by cations such as zinc, copper, magnesium and others (Roberts et al. 2006, Coddou et al. 2011, Coddou et al. 2011, Chataigneau et al. 2013).
Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Inés Maestro, Patricia Boya, Ana Martinez
Protein kinases are currently one of the most important classes of drug targets in the pharmaceutical industry. Kinases phosphorylate other proteins, thereby activating or inhibiting their function, with consequent impacts on a host of different biological processes [7]. Autophagy is a dynamic and highly regulated cellular process, involving many phosphorylation events that are catalyzed by protein kinases [8], including autophagosome formation. This key initial event is mediated by the mammalian serine/threonine kinase (STK), known as ULK1 [9]. Although STKs account for the majority of kinases discovered to date, few STK inhibitors have been approved for therapeutic use in humans. However, these compounds are being using in research to reveal the crucial roles of different STKs in major signaling pathways, and will likely be developed as drug candidates for testing in clinical trials. Examples include inhibitors of serum- and glucocorticoid-induced kinase 1 (SGK1), a STK that plays an important role in stress conditions and inhibits autophagy by acting upstream of ULK1, most likely by regulating gene expression [10].
Related Knowledge Centers
- Bacteria
- Catalysis
- Genome
- Phosphate
- Protein Phosphorylation
- Signal Transduction
- Kinase
- Substrate
- Genome
- Serine/Threonine-Specific Protein Kinase
- Tyrosine Kinase