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.

Combination of type I and type II MET tyrosine kinase inhibitors as therapeutic approach to prevent resistance

2021 ◽  
pp. molcanther.0344.2021
Author(s):  
Magda Bahcall ◽  
Cloud P. Paweletz ◽  
Yanan Kuang ◽  
Luke J. Taus ◽  
Taebo Sim ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Therapeutic Approach ◽  
Kinase Inhibitors ◽  
Type I ◽  
Type Ii

scholarly journals Potential role of tyrosine kinase inhibitors during primary HIV-1 infection

2017 ◽  
Vol 15 (5) ◽  
pp. 421-423 ◽  
Author(s):  
Juan Ambrosioni ◽  
Mayte Coiras ◽  
José Alcamí ◽  
José M. Miró
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Potential Role ◽  
Kinase Inhibitors ◽  
Hiv 1

Tyrosine kinase inhibitors enhance GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells

1997 ◽  
Vol 152 (2) ◽  
pp. 193-199 ◽  
Author(s):  
T Ogiwara ◽  
C L Chik ◽  
A K Ho
Keyword(s):  
Tyrosine Kinase ◽  
Cholera Toxin ◽  
Tyrosine Kinase Inhibitors ◽  
Anterior Pituitary ◽  
Kinase Inhibitors ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Camp Accumulation ◽  
Anterior Pituitary Cells ◽  
Site Of Action

Abstract In this study, the role of tyrosine phosphorylation in agonist-stimulated cAMP accumulation and GH release in rat anterior pituitary cells was investigated. It was found that genistein, a tyrosine kinase inhibitor, while having no effect on its own, potentiated GHRH-stimulated cAMP accumulation in a concentration-dependent manner. In comparison, daidzein, an inactive analogue of genistein, was ineffective and vanadate, a phosphotyrosine phosphatase inhibitor, reduced GHRH-stimulated cAMP accumulation. Additional structurally unrelated tyrosine kinase inhibitors, erbstatin and tyrphostins, also potentiated GHRH-stimulated cAMP accumulation. To determine the site of action of the tyrosine kinase inhibitors, pituitary adenylate cyclase-activating polypeptide (PACAP), cholera toxin and forskolin were used to increase cAMP accumulation. Genistein enhanced the PACAP-, cholera toxin- or forskolin-stimulated cAMP accumulation, suggesting that the site of action is at the post-receptor level. However, when the phosphodiesterase was inhibited by isobutylmethylxanthine, genistein did not potentiate and vanadate did not inhibit GHRH-stimulated cAMP accumulation, indicating that phosphodiesterase is a probable site of action for the inhibitor. Genistein and erbstatin also enhanced GHRH-stimulated GH release and the effect of vanadate was inhibitory. These results indicate that tyrosine kinase inhibitors enhance cAMP accumulation through their action on phosphodiesterase activity in rat anterior pituitary cells and the tyrosine kinase pathway appears to be involved in the control of GH release. Journal of Endocrinology (1997) 152, 193–199

Tyrosine kinase inhibitors and antioxidants modulate NF-κB and NOS-II induction in retinal epithelial cells

1998 ◽  
Vol 275 (1) ◽  
pp. C208-C215 ◽  
Author(s):  
Violaine Faure ◽  
Yves Courtois ◽  
Olivier Goureau
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Nuclear Translocation ◽  
Pyrrolidine Dithiocarbamate ◽  
Dependent Manner ◽  
Mrna Accumulation ◽  
Ifn Γ

Bovine retinal pigmented epithelial (RPE) cells express an inducible nitric oxide synthase (NOS-II) after activation with interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Experiments were performed to investigate the effects of tyrosine kinase inhibitors (genistein and herbimycin A) and antioxidants [pyrrolidine dithiocarbamate (PDTC) and butyl hydroxyanisol] on NOS-II induction. The LPS-IFN-γ-induced nitrite release was inhibited in a concentration-dependent manner by these compounds. Analysis by Northern blot showed that this inhibitory effect correlated with a decrease in NOS-II mRNA accumulation. Analysis by electrophoretic mobility shift assay of the activation of the transcription factor nuclear factor-κB (NF-κB) involved in NOS-II induction demonstrated that LPS alone or combined with IFN-γ induced NF-κB binding. NF-κB activation was not changed by the presence of tyrosine kinase inhibitors but was totally prevented by PDTC pretreatment. Immunocytochemistry experiments confirmed the reduction of the nuclear translocation of NF-κB only by PDTC. Our results demonstrated the existence in retinal pigmented epithelial cells of different intracellular signaling pathways in NOS-II induction, since tyrosine kinase inhibitors blocked NOS-II mRNA accumulation without inhibiting NF-κB activation. Furthermore, the LPS-IFN-γ-induced NOS-II mRNA accumulation was sensitive to cycloheximide, suggesting that, in addition to NF-κB, transcriptional factors that require new protein synthesis are involved in NOS-II induction.

Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

2020 ◽  
Vol 56 (4) ◽  
pp. 2000279 ◽  
Author(s):  
Jason Weatherald ◽  
Louise Bondeelle ◽  
Marie-Camille Chaumais ◽  
Christophe Guignabert ◽  
Laurent Savale ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Chronic Myelogenous Leukaemia ◽  
Pulmonary Complications ◽  
Myelogenous Leukaemia ◽  
Dependent Manner ◽  
Pulmonary Arterial

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.

scholarly journals Effect of tyrosine kinase inhibitors on the cytotoxic activity against HIV-1 infection

2017 ◽  
Vol 3 ◽  
pp. 51-52
Author(s):  
S. Rodríguez-Mora ◽  
G. Bautista ◽  
E. Mateos ◽  
V. García ◽  
J.L. Steegmann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cytotoxic Activity ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Hiv 1

scholarly journals Purification of PKC-I, an endogenous protein kinase C inhibitor, and types II and III protein kinase C isoenzymes from human neutrophils

1992 ◽  
Vol 284 (2) ◽  
pp. 399-405 ◽  
Author(s):  
K J Balazovich ◽  
E L McEwen ◽  
M L Lutzke ◽  
L A Boxer ◽  
T White
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Human Neutrophils ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Western Blots ◽  
Type Iii ◽  
Kinase C ◽  
Endogenous Protein

Human neutrophil protein kinase C (PKC) activity is inhibited by an endogenous protein found primarily in the pellet fraction from homogenized specific granules, which was both heat- and proteinase-sensitive [Balazovich, Smolen & Boxer (1986) J. Immunol. 137, 1665-1673]. We now report that two PKC isoenzymes and the endogenous PKC inhibitor, which we named PKC-I, were purified from human neutrophils. A neutrophil soluble fraction that was subjected to DEAE-Sephacel chromatography yielded highly enriched PKC because, by definition, enzymic activity was strictly dependent on Ca2+ and phosphatidylserine. Hydroxyapatite chromatography resolved two peaks of PKC activity. Type II and Type III PKC isoenzymes were each identified on Western blots by using isoenzyme-specific monoclonal antibodies. Unlike rat brain, from which PKC isoenzymes were also purified, Type I PKC was not detected in human neutrophils. Western blots indicated that both Type II and Type III PKC isoenzymes had molecular masses near 80 kDa. In agreement with other reports, PKC was autophosphorylated in vitro. PKC-I, an endogenous neutrophil inhibitor of PKC, was purified to apparent homogeneity by DEAE-Sephacel and S-400 Sephacel chromatography. PKC-I had a molecular mass of 41 kDa. PKC-I inhibited purified PKC activity stimulated by 1,2-diacylglycerols in a concentration-dependent manner, and inhibited PKC-dependent phosphorylation of proteins present in neutrophil cytosol.

The Immune-Inhibitory Receptor Osteoactivin Is up-Regulated In Monocyte-Derived Dendritic Cells Upon Exposure to Tyrosine Kinase Inhibitors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1733-1733
Author(s):  
Michael Gutknecht ◽  
Mark-Alexander Schwarzbich ◽  
Julia Salih ◽  
Lothar Kanz ◽  
Helmut R. Salih ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Tyrosine Kinase Inhibitors ◽  
T Cell Activation ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Type I

Abstract Abstract 1733 Targeted therapies with tyrosine kinase inhibitors (TKI) have significantly improved the treatment of cancer patients. Ex vivo generated dendritic cells (DC) are commonly used in immunotherapeutic strategies due to their unique ability to initiate adaptive immune responses, and multiple approaches presently aim to combine targeted therapies with immunotherapy. However, as many kinases targeted by TKI are, besides governing tumor cell growth, also involved in the activation of DC, TKI therapy may cause immunoinhibitory side effects. Osteoactivin (GPNMB, DC-HIL) is a type I transmembrane glycoprotein that is detected abundantly in DC but not in monocytes. Its expression on antigen-presenting cells can inhibit T cell activation by binding syndecan-4 (SD-4) on T cells. Here we investigated the effect of the BCR/ABL TKI imatinib, dasatinib and nilotinib, which are approved for the treatment of CML, on the expression of osteoactivin and DC functions. DC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Imatinib, nilotinib or dasatinib were added to the culture medium every second day starting from the first day of culture. In some experiments, toll-like receptor (TLR) ligands (L) (LPS (TLR4L), pam3Cys (TLR2L), poly I:C (TLR3L) or R848 (TLR7/8L) were added on day 6 of culture for maturation of DC. We found that DC generated in the presence of therapeutic concentrations of all three TKI displayed an altered phenotype. Imatinib caused significantly reduced expression of the typical DC markers CD1a, CD83 and the co-stimulatory molecule CD86. Nilotinib reduced the expression of CD1a, CD83, CD86 and the DC-specific C-type lectin receptor DC-SIGN (CD209). Dasatinib impaired expression of CD1a, CD83, CD86, CD80 and DC-SIGN. Most notably, we observed excessive up-regulation of osteoactivin on DC upon treatment with all three TKI. Interestingly, incubation with the immunosuppressive and anti-inflammatory cytokine IL-10 also resulted in osteoactivin over-expression. In line with osteoactivin up-regulation, exposure to TKI resulted in reduced stimulatory capacity of DC in MLR with allogenic T cells that could be restored by addition of blocking anti-osteoactivin antibody. In summary, our data demonstrate that up-regulation of osteoactivin is critically involved in the inhibition of DC function upon TKI exposure. These findings are of great importance for future combinatory approaches using TKI and DC-based immunotherapy and indicate that inhibition of osteoactivin expression or function may serve as a novel strategy to enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

Tyrosine kinase inhibitors block the glucocorticoid stimulation of prostaglandin endoperoxide H synthase expression in amnion cells

1999 ◽  
Vol 77 (2) ◽  
pp. 138-142 ◽  
Author(s):  
Tamas Zakar ◽  
Jane E Mijovic ◽  
Damyanti Bhardwaj ◽  
David M Olson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Prostaglandin Endoperoxide ◽  
Herbimycin A ◽  
Cell Extracts ◽  
Endoperoxide H Synthase ◽  
Stimulation Of

Human amnion cells in primary culture respond to glucocorticoids in a characteristic fashion by the increased expression of the inducible prostaglandin endoperoxide H synthase isoenzyme, PGHS-2. Since PGHS-2 induction by agonists generally involves tyrosine kinases, we examined the possibility that the glucocorticoid stimulation of PGHS-2 in the amnion cells is tyrosine kinase dependent. PGHS-2 expression was stimulated in confluent, serum-starved amnion cells with dexamethasone, and the effect of the tyrosine kinase inhibitors herbimycin A and tyrphostins AG126, AG1288, and A1 on enzyme activity induction was determined. All four inhibitors blocked the increase of PGHS activity in a concentration-dependent manner with IC50 values of 0.077 ± 0.05, 15.38 ± 5.14, 20.91 ± 3.1, and 29.77 ± 8.21 µM, respectively (mean ± SE, n = 4). Dexamethasone increased (approximately twofold) the tyrosine phosphorylation of 120-, 110-, and 77-kDa proteins in cell extracts, and herbimycin A selectively blocked the phosphorylation of the 110-kDa phosphoprotein. The stimulation of the steady-state level of PGHS-2 mRNA by dexamethasone was also inhibited by herbimycin A. These results suggest that glucocorticoids induce PGHS-2 expression in amnion cells with the involvement of tyrosine kinase(s). The role of tyrosine kinase dependent mechanisms in the control of amnion cell responsiveness to corticosteroids remains to be established.Key words: amnion, glucocorticoid, tyrosine kinase, prostaglandin H synthase.

Role of protein tyrosine phosphorylation in H2O2-induced activation of endothelial cell phospholipase D

1996 ◽  
Vol 271 (3) ◽  
pp. L400-L408 ◽  
Author(s):  
V. Natarajan ◽  
S. Vepa ◽  
R. S. Verma ◽  
W. M. Scribner
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinase Inhibitors ◽  
Phospholipase D ◽  
Kinase Inhibitors ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Protein Tyrosine Phosphorylation ◽  
Protein Tyrosine

Oxidant-induced activation of phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAEC) is independent of protein kinase C and calcium. In the present study, the effects of tyrosine kinase and protein tyrosine phosphatase (PTPase) inhibitors on hydrogen peroxide (H2O2)-induced PLD activation and protein tyrosine phosphorylation were examined in BPAEC. Pretreatment of BPAEC with putative tyrosine kinase inhibitors genistein, tyrphostin, and herbimycin attenuated H2O2 (1 mM)-induced PLD activation. The inhibitory effect of the tyrosine kinase inhibitors was highly specific for H2O2-induced modulation and showed no effect on PLD activation mediated by 12-O-tetradecanoylphorbol 13-acetate or bradykinin. Furthermore, addition of H2O2 increased in a time-dependent manner tyrosine phosphorylation of several proteins (17-200 kDa), as determined by immunoblot analysis with antiphosphotyrosine antibodies. H2O2-mediated protein tyrosine phosphorylation preceded PLD activation, and a good correlation was observed on the effect of genistein in H2O2-induced PLD activation and protein tyrosine phosphorylation. Addition of vanadate, a phosphotyrosine phosphatase inhibitor, synergistically increased both PLD activation and protein tyrosine phosphorylation mediated by H2O2. Moreover, vanadate by itself had minimal effect on basal PLD activity in BPAEC; however, at 10 microM vanadate, an increase in protein tyrosine phosphorylation was observed. In addition to vanadate, phenylarsine oxide and diamide potentiated H2O2-induced PLD activation. These results suggest that tyrosine kinase activation may be involved in H2O2-induced PLD activation in vascular endothelial cells.

Sign in / Sign up

Export Citation Format

Share Document