scholarly journals Activation of Src kinase Lyn by the Kaposi sarcoma–associated herpesvirus K1 protein: implications for lymphomagenesis

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3987-3994 ◽  
Author(s):  
Om Prakash ◽  
O. Rama Swamy ◽  
Xiochang Peng ◽  
Zhen-Ya Tang ◽  
Li Li ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Kaposi Sarcoma ◽  
B Cell Lymphoma ◽  
Proliferation Index ◽  
Kinase Activation ◽  
Transmembrane Glycoprotein ◽  
Lyn Kinase ◽  
A Cell

AbstractThe K1 gene of Kaposi sarcoma–associated herpesvirus (KSHV) encodes a transmembrane glycoprotein bearing a functional immunoreceptor tyrosine-based activation motif (ITAM). Previously, we reported that the K1 protein induced plasmablastic lymphomas in K1 transgenic mice, and that these lymphomas showed enhanced Lyn kinase activity. Here, we report that systemic administration of the nuclear factor kappa B (NF-κB) inhibitor Bay 11-7085 or an anti–vascular endothelial growth factor (VEGF) antibody significantly reduced K1 lymphoma growth in nude mice. Furthermore, in KVL-1 cells, a cell line derived from a K1 lymphoma, inhibition of Lyn kinase activity by the Src kinase inhibitor PP2 decreased VEGF induction, NF-κB activity, and the cell proliferation index by 50% to 75%. In contrast, human B-cell lymphoma BJAB cells expressing K1, but not the ITAM sequence–deleted mutant K1, showed a marked increase in Lyn kinase activity with concomitant VEGF induction and NF-κB activation, indicating that ITAM sequences were required for the Lyn kinase–mediated activation of these factors. Our results suggested that K1-mediated constitutive Lyn kinase activation in K1 lymphoma cells is crucial for the production of VEGF and NF-κB activation, both strongly implicated in the development of KSHV-induced lymphoproliferative disorders.

Regulation of protein kinase by vasopressin in renal medulla in situ

1977 ◽  
Vol 232 (1) ◽  
pp. F50-F57
Author(s):  
T. P. Dousa ◽  
L. D. Barnes
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Renal Medulla ◽  
Protein Kinase Activity ◽  
Kinase Activation ◽  
Heat Stable ◽  
Protein Kinase Activation ◽  
Heat Stable Protein

Results of this study demonstrate that vasopressin activates protein kinase in intact renal medullary cells as detected by measurement of the (-cyclic AMP/+cyclic AMP) protein kinase activity ratios in freshly prepared tissue extracts (40,000 X g supernates) from bovine renal medullary slices. The activation of protein kinase was specific for vasopressin since parathyroid hormone, histamine, angiotensin II, or the inactive analog of vasopressin did not activate protein kinase. There was a direct correlation between the extent of protein kinase activation and the elevation in tissue levels of cyclic AMP elicited by increasing doses of vasopressin or with an increase in incubation time. The elevation of tissue cyclic AMP level and maximum activation of protein kinase reached maximum level at a vasopressin concentration of about 2 X 10(-9) M. Incubation of slices with vasopressin caused a dose-dependent decrease in the cyclic AMP-dependent protein kinase activity in the 40,000 X g supernate of homogenate from the renal medullary slices. This effect of vasopressin was specific for protein kinase since activity of lactate dehydrogenase or a specific [3H]colchicine-binding activity was not affected, and the decrease in the protein kinase was not due to the accumulation of a heat-stable protein kinase inhibitor. There was an increase in protein kinase was not due to the accumulation of a heat-stable protein kinase inhibitor. There was an increase in protein kinase activity extracted from 40,000 X g pellets of homogenate prepared from slices exposed to vasopressin. Results thus provide evidence that cyclic AMP-mediated protein kinase activation in the intact cells is an integral part of cellular response of the mammalian renal medulla to vasopressin.

Dasatinib (BMS-354825) is active in Philadelphia chromosome–positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 497-499 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Claude Nicaise ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Src Kinase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Kinase Activation ◽  
Complete Hematologic Response

Abstract Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl–mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.

scholarly journals Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2329-2338 ◽  
Author(s):  
Heiko Konig ◽  
Tessa L. Holyoake ◽  
Ravi Bhatia
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Selective Inhibition ◽  
Curative Therapy ◽  
Abl Kinase ◽  
Mapk Activity ◽  
High Concentrations

Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34+ cells and inhibited Src phosphorylation more potently than imatinib. However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However, SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared with imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.

ACTIVATION OF MAP KINASE ASSOCIATED WITH THE PRIMING EFFECT OF LHRH

1994 ◽  
Vol 140 (2) ◽  
pp. R15-R18 ◽  
Author(s):  
R. Mitchell ◽  
P.J. Sim ◽  
T. Leslie ◽  
M.S. Johnson ◽  
F.J. Thomson
Keyword(s):  
Map Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Protein Synthesis Inhibitor ◽  
High Potency ◽  
Synthesis Inhibitor ◽  
Kinase Activation ◽  
Gf 109203X ◽  
Lh Release ◽  
Kinase Activity Assay

ABSTRACT A MAP kinase activity assay was developed to determine whether the LHRH receptor could activate this enzyme (particularly during LHRH priming). In anterior pituitary tissue from prooestrous rats LHRH caused concentration-dependent activation of MAP kinase after 5-10 min and continued for up to 60 min of incubation. The magnitude of this response correlated with that of LHRH priming on various days of the oestrous cycle but not with the magnitude of 1st hour (unprimed) LHRH-induced LH release. The response to LHRH was mimicked by a phorbol ester but not by ionomycin and was blocked with high potency by GF 109203X but not by H7 (in a similar manner to the PKC species that mediates LHRH priming). Neither the tyrosine kinase inhibitor lavendustin A nor the protein synthesis inhibitor cycloheximide blocked LHRH-induced MAP kinase activation. The possible functional significance of MAP kinase activation in gonadotrophs is considered with respect to LHRH priming.

Relative contribution of G-protein-coupled pathways to protease-activated receptor-mediated Akt phosphorylation in platelets

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 947-954 ◽  
Author(s):  
Soochong Kim ◽  
Jianguo Jin ◽  
Satya P. Kunapuli
Keyword(s):  
G Protein ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Rho Kinase ◽  
Protease Activated Receptors ◽  
Kinase Activation ◽  
Akt Phosphorylation ◽  
Relative Contribution ◽  
Rho Kinase Inhibitor ◽  
G Protein Coupled

AbstractProtease-activated receptors (PARs) activate Gq and G12/13 pathways, as well as Akt (protein kinase B [PKB/Akt]) in platelets. However, the relative contribution of different G-protein pathways to Akt phosphorylation has not been elucidated. We investigated the contribution of Gq and G12/13 to Gi/Gz-mediated Akt phosphorylation downstream of PAR activation. Selective G12/13 activation failed to cause Akt phosphorylation in human and Gαq-deficient mouse platelets. However, supplementing Gi/Gz signaling to G12/13 caused significant increase in Akt phosphorylation, confirming that G12/13 potentiates Akt phosphorylation. Inhibition of PAR-mediated Akt phosphorylation in the presence of the Gq-selective inhibitor YM-254890 was restored to the normal extent achieved by PAR agonists if supplemented with Gi signaling, indicating that Gq does not have any direct effect on Akt phosphorylation. Selective G12/13 activation resulted in Src kinase activation, and Akt phosphorylation induced by costimulation of G12/13 and Gi/Gz was inhibited by a Src kinase inhibitor but not by a Rho kinase inhibitor. These data demonstrate that G12/13, but not Gq, is essential for thrombin-induced Akt phosphorylation in platelets, whereas Gq indirectly contributes to Akt phosphorylation through Gi stimulation by secreted ADP. G12/13 activation might mediate its potentiating effect through Src activation, and Src kinases play an important role in thrombin-mediated Akt phosphorylation.

Abstract 3571: Evidence for Rho-Kinase Activation in Patients with Pulmonary Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Zhulanqiqige Doe ◽  
Yoshihiro Fukumoto ◽  
Aya Takaki ◽  
Shunsuke Tawara ◽  
Junko Ohashi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Heart Diseases ◽  
Pulmonary Arteries ◽  
Connective Tissue Diseases ◽  
Rho Kinase ◽  
Kinase Activation ◽  
And Gender

Pulmonary hypertension (PH) still remains a fatal disease characterized by hyperconstriction and remodeling of pulmonary arteries (PA). We and others have previously demonstrated that long-term inhibition of Rho-kinase is useful for treatment of PH in animal models, however, it remains to be examined whether Rho-kinase is actually activated in patients with PH. First, we examined whether Rho-kinase activity is enhanced in circulating neutrophils from 40 healthy age- and gender-matched controls and 40 PH patients with various etiologies, including idiopathic PAH (n=18), and PH associated with connective tissue diseases (n=8), congenital heart diseases (n=7), or chronic thromboembolism (n=7). We measured total and phosphorylated forms of myosin binding subunit (MBS), a substrate of Rho-kinase, by Western blotting, and defined the p-MBS/t-MBS ratio as an index of systemic Rho-kinaes activity. Next, we examined Rho-kinase activity by immunostaining in lung tissues from 5 controls and 5 IPAH obtained during lung surgery and transplantation, respectively. Finally, we examined vascular responses of isolated small PA from those subjects in vitro. Systemic Rho-kinase activity was significantly increased in the PAH patients compared with the controls (P<0.0001). Among the 4 subgroups of PH, Rho-kinase activity was significantly increased in all except for PH with thromboembolism (P<0.05). Significant correlations were noted between Rho-kinase activity and mean PA pressure, pulmonary vascular resistance, and duration of the disorder in the PH patients (all P<0.05). Rho-kinase expression in small PA and Rho-kinase activity in the lung tissue also were significantly increased in the PAH patients compared the controls (both P<0.0001). Endothelium-dependent relaxations were markedly impaired and serotonin-induced contractions were markedly enhanced in the PAH patients compared with the controls, and the hypercontractions were abolished in the presence of hydroxyfasudil, a specific Rho-kinase inhibitor (all P<0.01). These results provide the first direct evidence for Rho-kinase activation in patients with PH, confirming the therapeutic importance of Rho-kinase in the treatment of PH in humans.

Endothelial contraction and monolayer hyperpermeability are regulated by Src kinase

2003 ◽  
Vol 284 (3) ◽  
pp. H994-H1002 ◽  
Author(s):  
David R. Mucha ◽  
Carter L. Myers ◽  
Richard C. Schaeffer
Keyword(s):  
Tyrosine Phosphorylation ◽  
Myosin Light Chain ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Src Kinase ◽  
Endothelial Monolayer ◽  
Herbimycin A ◽  
Barrier Formation ◽  
Monolayer Barrier Function

Endothelial monolayer hyperpermeability is regulated by a myosin light chain phosphorylation (MLCP)-dependent contractile mechanism. In this study, we tested the role of Src-dependent tyrosine phosphorylation to modulate endothelial contraction and monolayer barrier function with the use of the myosin phosphatase inhibitor calyculin A (CalA) to directly elevate MLCP with the Src family tyrosine kinase inhibitor herbimycin A (HA) in bovine pulmonary artery endothelial cells (EC). CalA stimulated an increase in MLCP, Src kinase activity, an increase in the tyrosine phosphorylation of paxillin and focal adhesion (FA) kinase (p125FAK), and monolayer hyperpermeability. Microscopic examination of CalA-treated EC revealed a contractile morphology characterized by peripheral contractile bands of actomyosin filaments and stress fibers linked to phosphotyrosine-containing FAs. These CalA-dependent events were HA sensitive. HA alone stimulated an improvement in monolayer barrier formation by reducing the levels of MLCP and phosphotyrosine-containing proteins and the number of large paracellular holes. These data show that Src kinase plays an important role in regulating monolayer hyperpermeability through adjustments in tyrosine phosphorylation, MLCP, and EC contraction.

scholarly journals Lyn Kinase Activity Is the Predominant Cellular Src Kinase Activity in Glioblastoma Tumor Cells

2005 ◽  
Vol 65 (13) ◽  
pp. 5535-5543 ◽  
Author(s):  
Michelle R. Stettner ◽  
Wenquan Wang ◽  
L. Burton Nabors ◽  
Suman Bharara ◽  
Daniel C. Flynn ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Kinase Activity ◽  
Src Kinase ◽  
Lyn Kinase

scholarly journals Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in an Ultra-Rare Disease

2021 ◽  
Author(s):  
Kevin Peikert ◽  
Hannes Glaß ◽  
Enrica Federti ◽  
Alessandro Matte ◽  
Lisann Pelzl ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Actin Cytoskeleton ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Treatment Time ◽  
Treatment Approach ◽  
Clinical Effects ◽  
Lyn Kinase

ABSTRACTBackgroundChorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms and therefore represents a promising drug target.MethodsWe evaluated an individual off-label treatment with the FDA-approved tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8-50.4 weeks) of three ChAc patients. Alongside with a thorough safety monitoring, we assessed motor and non-motor scales (e.g. MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g. serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells).ResultsDasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels and acanthocyte count did not reveal consistent effects. However, reduction of initially elevated Lyn kinase activity and accumulated autophagy markers as well as partial restoration of actin cytoskeleton was found in red blood cells.DiscussionWe report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. Here, we suggest a panel of outcome parameters for future clinical trials in ChAc.

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