scholarly journals Inhibition of RAF dimers: it takes two to tango

2020 ◽  
Author(s):  
Frazer A. Cook ◽  
Simon J. Cook
Keyword(s):  
Cell Proliferation ◽  
Kinase Inhibitors ◽  
The Other ◽  
Type I ◽  
Type Ii ◽  
Wild Type ◽  
Dimer Formation ◽  
Effective Inhibition ◽  
Mutant Cells ◽  
Active Class

The RAS-regulated RAF–MEK1/2–ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed “paradox breakers” which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins

scholarly journals Impact of Type II LRRK2 inhibitors on signalling and mitophagy

2021 ◽  
Author(s):  
Anna Tasegian ◽  
Francois Singh ◽  
Ian Ganley ◽  
Alastair D Reith ◽  
Dario R Alessi
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Domain ◽  
Type I ◽  
Phosphorylation Sites ◽  
Type Ii ◽  
Potential Treatment ◽  
Wild Type ◽  
Closed Conformation ◽  
Lrrk2 Kinase ◽  
Physiological Substrates

Much effort has been devoted to the development of selective inhibitors of the LRRK2 as a potential treatment for LRRK2 driven Parkinson's disease. In this study we first compare the properties of Type I (GSK3357679A and MLi-2) and Type II (Ponatinib and GZD-824) kinase inhibitors that bind to the closed or open conformations of the LRRK2 kinase domain, respectively. We show that Type I and Type II inhibitors suppress phosphorylation of Rab10 and Rab12, key physiological substrates of LRRK2 and also promote mitophagy, a process suppressed by LRRK2. Unexpectedly, we strikingly find that Type II inhibitors, in contrast to Type I compounds, fail to induce dephosphorylation of a set of well-studied LRRK2 biomarker phosphorylation sites at the N-terminal region of LRRK2, including Ser935. Type II inhibitors also display higher potency towards wild type LRRK2 compared to pathogenic mutants. These findings emphasize that the biomarker phosphorylation sites on LRRK2 are likely reporting on the open-closed conformation of LRRK2 kinase and that only inhibitors which stabilize the closed conformation induce dephosphorylation of these biomarker sites. Our observations provide a framework of knowledge to aide with the development of more selective Type II LRRK2 inhibitors.

Two Different UGT1A1 Mutations causing Crigler–Najjar Syndrome types I and II in an Iranian Family

2015 ◽  
Vol 24 (4) ◽  
pp. 523-526 ◽  
Author(s):  
Yoshihiro Maruo ◽  
Mahdiyeh Behnam ◽  
Shinichi Ikushiro ◽  
Sayuri Nakahara ◽  
Narges Nouri ◽  
...  
Keyword(s):  
Serum Bilirubin ◽  
Total Serum Bilirubin ◽  
Total Serum ◽  
Compound Heterozygous ◽  
Type I ◽  
Syndrome Type ◽  
Type Ii ◽  
Wild Type ◽  
Iranian Family ◽  
Udp Glucuronosyltransferase

Background: Crigler–Najjar syndrome type I (CN-1) and type II (CN-2) are rare hereditary unconjugated hyperbilirubinemia disorders. However, there have been no reports regarding the co-existence of CN-1 and CN-2 in one family. We experienced a case of an Iranian family that included members with either CN-1 or CN-2. Genetic analysis revealed a mutation in the bilirubin UDP-glucuronosyltransferase (UGT1A1) gene that resulted in residual enzymatic activity.Case report: The female proband developed severe hyperbilirubinemia [total serum bilirubin concentration (TB) = 34.8 mg/dL] with bilirubin encephalopathy (kernicterus) and died after liver transplantation. Her family history included a cousin with kernicterus (TB = 30.0 mg/dL) diagnosed as CN-1. Her great grandfather (TB unknown) and uncle (TB = 23.0 mg/dL) developed jaundice, but without any treatment, they remained healthy as CN-2. Results: The affected cousin was homozygous for a novel frameshift mutation (c.381insGG, p.C127WfsX23). The affected uncle was compound heterozygous for p.C127WfsX23 and p.V225G linked with A(TA)7TAA. p.V225G-UGT1A1 reduced glucuronidation activity to 60% of wild-type. Thus, linkage of A(TA)7TAA and p.V225G might reduce UGT1A1 activity to 18%–36 % of the wild-type. Conclusion: Genetic and in vitro expression analyses are useful for accurate genetic counseling for a family with a history of both CN-1 and CN-2. Abbreviations: CN-1: Crigler–Najjar syndrome type I; CN-2: Crigler–Najjar syndrome type II; GS: Gilbert syndrome; UGT1A1: bilirubin UDP-glucuronosyltransferase; WT: Wild type; TB: total serum bilirubin.

Burn-in procedures for a generalized model

2001 ◽  
Vol 38 (02) ◽  
pp. 542-553 ◽  
Author(s):  
Ji Hwan Cha
Keyword(s):  
The Other ◽  
Replacement Policy ◽  
Type I ◽  
Type Ii ◽  
Failure Model ◽  
Minimal Repair ◽  
Optimal Replacement ◽  
Complete Repair ◽  
Optimal Replacement Policy ◽  
Type Of Failure

In this paper two burn-in procedures for a general failure model are considered. There are two types of failure in the general failure model. One is Type I failure (minor failure) which can be removed by a minimal repair or a complete repair and the other is Type II failure (catastrophic failure) which can be removed only by a complete repair. During a burn-in process, with burn-in Procedure I, the failed component is repaired completely regardless of the type of failure, whereas, with burn-in Procedure II, only minimal repair is done for the Type I failure and a complete repair is performed for the Type II failure. In field use, the component is replaced by a new burned-in component at the ‘field use age’ T or at the time of the first Type II failure, whichever occurs first. Under the model, the problems of determining optimal burn-in time and optimal replacement policy are considered. The two burn-in procedures are compared in cases when both the procedures are applicable.

Electrophysiological Characteristics of Classes of Neuron in the HVc of the Zebra Finch

1998 ◽  
Vol 80 (2) ◽  
pp. 914-923 ◽  
Author(s):  
Michinori Kubota ◽  
Ikuo Taniguchi
Keyword(s):  
Action Potential ◽  
Zebra Finch ◽  
Action Potential Duration ◽  
The Other ◽  
Time Dependent ◽  
Inward Rectification ◽  
Type I ◽  
Type Ii ◽  
Type Iii ◽  
Type Iv

Kubota, Michinori and Ikuo Taniguchi. Electrophysiological characteristics of classes of neuron in the HVc of the zebra finch. J. Neurophysiol. 80: 914–923, 1998. Whole cell recordings were made from zebra finch HVc neurons in slice preparations. Four distinct classes of neuron were found on the basis of their electrophysiological properties. The morphological characteristics of some of these neurons were also examined by intracellular injection of Lucifer yellow. Type I neurons (21 of 65 cells) had longer time-to-peak of an afterhyperpolarization following an action potential than the other classes. They exhibited both fast and time-dependent inward rectification and an initial high-frequency firing followed by a slower constant firing. Type I neurons had large somata and thick dendrites with many spines. The axons of some of the neurons in this class projected in the direction of area X of the parolfactory lobe. Type II neurons (30 of 65 cells) had a more negative resting membrane potential than the other classes. They exhibited fast inward rectification. Type II neurons could be divided into two subclasses by the absence (IIa; 22 cells) and the presence (IIb; 8 cells) of a low-threshold transient depolarization. Type IIa neurons had relatively small somata and thin, spiny dendrites. The axons of some of the neurons in this class projected in the direction of the robust nucleus of the archistriatum (RA). Type IIb neurons had relatively large somata and thick dendrites with many spines. Type III neurons (6 of 65 cells) had a shorter action-potential duration than the other classes. They exhibited prominent time-dependent inward rectification and a regular tonic firing with little or no accommodation. Type III neurons had beaded, aspiny dendrites. Type IV neurons (8 of 65 cells) had a longer action-potential duration, a much larger input resistance, and longer membrane time constant than the other classes. Type IV neurons had small somata and thin, short, sparsely spiny dendrites. The axons of some of the neurons in this class projected in the direction of the RA. These classes of neuron may play distinct roles in song production and representation in the HVc.

Aldosterone binding sites along nephron of Xenopus and rabbit

1989 ◽  
Vol 257 (1) ◽  
pp. R87-R95 ◽  
Author(s):  
A. Gnionsahe ◽  
M. Claire ◽  
N. Koechlin ◽  
J. P. Bonvalet ◽  
N. Farman
Keyword(s):  
Binding Sites ◽  
Direct Evidence ◽  
Distal Tubule ◽  
Distal Segment ◽  
The Other ◽  
Type I ◽  
Thick Ascending Limb ◽  
Type Ii ◽  
Straight Segment ◽  
Dry Film

Distal segment of several amphibians exhibits aldosterone-modulated ion transport properties. On the other hand, A6 cells, derived from Xenopus laevis (XL) kidney, are aldosterone sensitive. We examined the distribution of aldosterone binding sites in isolated tubules of XL compared with rabbit. After incubation with 2 nM [3H]aldosterone, microdissected tubular segments from proximal (PT), distal straight segment (DST), and flask cell collecting (CT) tubules from XL and from rabbit cortical thick ascending limb (CTAL), connecting (CNT), and collecting (CCD) tubules were processed for dry film autoradiography. In XL, specific nuclear labeling of type I (mineralocorticoid) sites was restricted to DST. Labeling of type II (glucocorticoid) sites was present all along the tubule. No specific cytoplasmic labeling was observed, except for type II sites in PT. In the rabbit, aldosterone binds to both type I and type II sites in the three tubular segments studied. In these segments, the binding was about fourfold higher than in DST of XL. These results bring direct evidence in designating the distal tubule of amphibians as a target epithelium for aldosterone. In addition, they suggest that A6 cell line may derive from DST of the Xenopus nephron.

Role of common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of murine mast cells

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2172-2180 ◽  
Author(s):  
Kotaro Suzuki ◽  
Hiroshi Nakajima ◽  
Norihiko Watanabe ◽  
Shin-ichiro Kagami ◽  
Akira Suto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Cytokine Receptor ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Wild Type ◽  
Peritoneal Mast Cells ◽  
The Common

Abstract The regulatory roles of the common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of mast cells were determined using γc-deficient (γc−) and Jak3-deficient (Jak3−) mice. Although the mast cells in γc− and Jak3− mice were morphologically indistinguishable from those in wild-type mice, the number of peritoneal mast cells was decreased in γc− and Jak3− mice as compared with that in wild-type mice. Among γc-related cytokines, interleukin (IL)-4 and IL-9, but not IL-2, IL-7, or IL-15, enhanced the proliferation and survival of bone marrow–derived mast cells (BMMCs) from wild-type mice. However, the effects of IL-4 and IL-9 were absent in BMMCs from γc− and Jak3−mice. In addition, IL-4Rα, γc, and Jak3, but not IL-2Rβ or IL-7Rα, were expressed in BMMCs. In contrast, IL-13 did not significantly induce the proliferation and survival of BMMCs even from wild-type mice, and IL-13Rα1 was not expressed in BMMCs. Furthermore, IL-4 phosphorylated the 65-kd isoform of Stat6 in BMMCs from wild-type mice but not from γc− and Jak3− mice. These results indicate that γc- and Jak3-dependent signaling is essential for IL-4– and IL-9–induced proliferation and survival of murine mast cells, that the effects of IL-4 are mediated by type I IL-4R and that type II IL-4R is absent on mast cells, and that IL-4 phosphorylates the 65-kd isoform of Stat6 in mast cells in a γc- and Jak3-dependent manner.

scholarly journals Toxin–Antitoxin Systems in Bacillus subtilis

Toxins ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 262 ◽  
Author(s):  
Sabine Brantl ◽  
Peter Müller
Keyword(s):  
Bacillus Subtilis ◽  
Physiological Role ◽  
Present Knowledge ◽  
The Other ◽  
Type I ◽  
Type Ii ◽  
Free Living ◽  
Bacterial Chromosomes ◽  
Maintenance Systems ◽  
Living Bacteria

Toxin–antitoxin (TA) systems were originally discovered as plasmid maintenance systems in a multitude of free-living bacteria, but were afterwards found to also be widespread in bacterial chromosomes. TA loci comprise two genes, one coding for a stable toxin whose overexpression kills the cell or causes growth stasis, and the other coding for an unstable antitoxin that counteracts toxin action. Of the currently known six types of TA systems, in Bacillus subtilis, so far only type I and type II TA systems were found, all encoded on the chromosome. Here, we review our present knowledge of these systems, the mechanisms of antitoxin and toxin action, and the regulation of their expression, and we discuss their evolution and possible physiological role.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

scholarly journals SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Matthew A. Szaniawski ◽  
Adam M. Spivak ◽  
James E. Cox ◽  
Jonathan L. Catrow ◽  
Timothy Hanley ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Restriction Factor ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Type Iii ◽  
Type Iii Ifn ◽  
Hiv 1

ABSTRACTMacrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.IMPORTANCEOur experimental results demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs. While IFN types I and II were potent inhibitors of HIV-1, type III IFN showed modest to undetectable activity. Regulation of SAMHD1 by IFNs involved changes in phosphorylation status but not in protein levels. Phosphorylation of SAMHD1 in macrophages occurred at least in part via CDK1. Tyrosine kinase inhibitors similarly induced SAMHD1 dephosphorylation, which protects macrophages from HIV-1 in a SAMHD1-dependent manner. SAMHD1 is a critical restriction factor regulating HIV-1 infection of macrophages.

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