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Genetic Control of Endotoxin Responsiveness: The Lps Gene Revisited
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Stefanie N. Vogel, Nayantara Bhat, Danielle Malo, Salman T. Qureshi
Vav was recently shown to be phosphorylated upon LPS stimulation (87), suggesting that it is one of the many kinases activated by LPS signaling. Vav is a proto-oncogene, and its gene product, Vav, has been suggested to play a role in the signal transduction pathways of hematopoietic cells (reviewed in Ref. 88). We have found that Vav becomes phosphorylated in LPS-treated macrophages earlier than the MAP kinases (J. Blanco, unpublished observation). Since early activation of Rsk kinase activity by phosphorylation is coordinate with the activation of MAP kinases, it has been suggested that Rsk acts to phosphorylate DNA-binding proteins and cytoplasmic proteins (reviewed in Ref. 89). Vav does not map to chromosome 4 (90), and another closely related gene, Vav2, was recently found to map close to the telomer of the long arm of human chromosome 9, far distal to the predicted location of the human Lps homolog (91). Rsk, also referred to as p90rsk or Rps6kal [ribosomal protein S6 kinase II alpha 1 (92)] has not been mapped in mouse; however, a human sequence called ribosomal protein S6 kinase 2 (93), which is 98% homologous to Rps6kal, has been mapped to human chromosome 1 in the region of the PAF receptor, i.e., homologous to distal mouse chromosome 4 (94). Thus, the finding of increased presence of these two kinases in the membranes of C3H/HeJ macrophages may suggest that their localization is affected by the Lpsd mutation.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The formation of irreversible covalent adducts may lead to off-target effects such as the reaction of acrylamides with hyperreactive Cys residues of other proteins potentially causing toxicity or an immune response. An alternative strategy in drug design therefore is reversible covalent inhibition where the covalent bond can be broken to release the inhibitor which is enabled by activated Michael acceptors as shown for the first time by Taunton and his group (Serafimova et al., 2013). They designed inhibitors modified with olefins bearing electron withdrawing groups for targeting non-conserved Cys side chains near the active site of the p90 ribosomal protein S6 kinase (serine threonine kinase; RSK), a potential target in lung adenocarcinomas (Poomakkoth et al., 2016). For this they modified the pyrrolopyrimidine scaffold of the known irreversible FMK/RSK-inhibitor (see scheme above) described previously by Cohen et al. (2005) with electron-deficient Michael acceptors; the electron-withdrawing nitrile group supports nucleophilic attack of the β-carbon as well as the elimination reaction by stabilizing the resulting carbanion. It could be shown that these inhibitors exclusively reacted with Cys436 of the kinase and that a mutation of Cys436 abolishes the inhibitory activity.
Emerging ergogenic aids for strength/power development
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
One pathway proposes that mechanical loading-induced skeletal muscle mechanotransduction increases synthesis of PA intracellularly via increased activity of diacylglycerol kinase (DAGK). PA may bind to Raf or mTORC1 and activates mTOR complex 1 (mTORC1), which stimulates downstream phosphorylation of ribosomal S6 kinase 1 (p70S6K) increasing protein synthesis. Activated mTORC1 phosphorylates translation inhibitor 4E-binding protein 1 (4E-BP1), releasing it from eukaryotic translation initiation factor 4E (eIF4E) increasing protein synthesis. PA in the blood may enter muscle and inhibit atrogenes (e.g., Atrogin-1, MuRF-1) and reduce protein breakdown. PA in the blood may also be hydrolyzed to LPA via A type phospholipases. LPA activates endothelial differentiation gene (EDG2) receptor resulting in G-protein mediated activation of Ras, Raf and mitogen-activated protein kinase (MEK) and extracellular regulated kinase (ERK) pathways. ERK1/2 inhibits tuberous sclerosis complex (TSC1/2) putting the Rheb in its GTP-bound state where it activates mTORC1. IGF-1/IGF-1 receptor interaction is also shown where ultimately Akt inhibits catabolic factors, TSC1/2 and stimulates mTORC1.
Ribosomopathies and cancer: pharmacological implications
Published in Expert Review of Clinical Pharmacology, 2022
Gazmend Temaj, Sarmistha Saha, Shpend Dragusha, Valon Ejupi, Brigitta Buttari, Elisabetta Profumo, Lule Beqa, Luciano Saso
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway participates in the phosphorylation of UBF, TIF1-A, and TFIIIB, and stimulates Pol I and Pol III. MAPK/ERK and PI3K/AKT signaling pathways activate c-Myc expression, which can increase ribosome biogenesis by promoting cell growth and division [38,39]. The mammalian target of rapamycin (mTOR) signaling pathway has also been shown to contribute to the activation of UBF, TIF1-A, Pol III TFIIIB, and TFIIID (transcription factors III B and IIID) [40–42]. mTOR is involved in the phosphorylation of eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP) and S6K (p70 ribosomal S6 kinase), events that modulate ribosome biogenesis, and translation of proteins that promote cell growth and division.
Targeting the integrated stress response in ophthalmology
Published in Current Eye Research, 2021
Hsiao-Sang Chu, Cornelia Peterson, Albert Jun, James Foster
There are no reported molecules that can directly bind and inhibit ATF4. Transcription factors are largely poor drug targets due to the inefficiency of small molecules to halt protein-DNA and protein-protein binding interfaces.153 However, ATF4 function is dependent on extensive post-translational modifications, particularly phosphorylation, that modulates its transcriptional activity and degradation. Ribosomal S6 kinase (RSK2) and protein kinase A (PKA) are two kinases that phosphorylate ATF4 and enhance its transcriptional activity.154,155 Reversible RSK2 inhibitors SL0101 and BI-D1870, and the irreversible inhibitor fmk have been developed.156–158 PKA inhibitors H-89 and KT 5720 are also available yet with low selectivity.159 Recently, another PKA antagonist Rp-8-Br-cAMPS with better selectivity has been developed.160 However, RSK2 and PKA both work on multiple protein responses for different cellular functions,161,162 and the use of these compounds as ATF4 inhibitors will need careful validation to support that the observed effects can be contributed to ATF4 inhibition. As yet, the application of ATF4 inhibitor in treating eye disease has not been reported.
The dawn of targeted therapies for triple negative breast cancer (TNBC): a snapshot of investigational drugs in phase I and II trials
Published in Expert Opinion on Investigational Drugs, 2020
My-my Huynh, Mary Rose Pambid, Aarthi Jayanthan, Andrew Dorr, Gerrit Los, Sandra E. Dunn
Recently, there has been considerable interest in targeting p90 ribosomal S6 kinase 2 (RSK2, RPS6KA3), downstream of MEK and ERK. RSK2 has emerged from siRNA functional screens and the use of RSK specific inhibitors in preclinical studies of TNBC cells in vitro and xenografts in vivo, show that RSK is an ideal target for TNBC [56,57]. RSK2 is a convergence point of the PDK-1 and MAPK pathways; more specifically it is phosphorylated by both ERK and PDK-1, transporting RSK2 from the cytoplasm into the nucleus to activate its targets. One of RSK2’s most important targets is Y-box binding protein-1 (YB-1), a transcription factor that is involved in cell survival, proliferation, and drug resistance [58,59]. RSK2 is highly expressed in TNBC and is a poor prognostic factor for patients [59]. A number of RSK inhibitors (RSKi) have been in pre-clinical development, but due to poor pharmacokinetics, they have not made it to the clinic [60]. Recently, however, the first-in-class oral RSKi PMD-026 began first-in-human studies and is currently in a phase I/Ib trial, in tandem development with a RSK2 companion diagnostic (NCT04115306) [61]. Given that RSK is downstream of MEK/ERK and PDK-1 in their respective signaling pathways, RSK has a limited set of substrates, therefore potentially fewer side effects are anticipated compared to inhibitors targeting kinases further upstream, such as MEK and ERK [56]. In particular, the inhibition of RSK, unlike MEK, does not cause activation of AKT, and therefore confers a distinct advantage because it does not activate this resistance pathway [62].