Platelet/Polymorphonuclear Leukocyte Interaction: P-Selectin Triggers Protein-Tyrosine Phosphorylation–Dependent CD11b/CD18 Adhesion: Role of PSGL-1 as a Signaling Molecule

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 876-885 ◽  
Author(s):  
Virgilio Evangelista ◽  
Stefano Manarini ◽  
Rita Sideri ◽  
Serenella Rotondo ◽  
Nicola Martelli ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinase Inhibitors ◽  
Polymorphonuclear Leukocyte ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chinese Hamster ◽  
Mixed Cell ◽  
Β2 Integrin ◽  
Activated Platelets

Polymorphonuclear leukocyte (PMN) adhesion to activated platelets is important for the recruitment of PMN at sites of vascular damage and thrombus formation. We have recently shown that binding of activated platelets to PMN in mixed cell suspensions under shear involves P-selectin and the activated β2-integrin CD11b/CD18. Integrin activation required signaling mechanisms that were sensitive to tyrosine kinase inhibitors.1 Here we show that mixing activated, paraformaldehyde (PFA)-fixed platelets with PMNs under shear conditions leads to rapid and fully reversible tyrosine phosphorylation of a prominent protein of 110 kD (P∼110). Phosphorylation was both Ca2+ and Mg2+ dependent and was blocked by antibodies against P-selectin or CD11b/CD18, suggesting that both adhesion molecules need to engage with their respective ligands to trigger phosphorylation of P∼110. The inhibition of P∼110 phosphorylation by tyrosine kinase inhibitors correlates with the inhibition of platelet/PMN aggregation. Similar effects were observed when platelets were substituted by P-selectin–transfected Chinese hamster ovary (CHO-P) cells or when PMN were stimulated with P-selectin–IgG fusion protein. CHO-P/PMN mixed-cell aggregation and P-selectin–IgG–triggered PMN/PMN aggregation as well as P∼110 phosphorylation were all blocked by antibodies against P-selectin or CD18. In each case PMN adhesion was sensitive to the tyrosine kinase inhibitor genistein. The antibody PL-1 against P-selectin glycoprotein ligand-1 (PSGL-1) blocked platelet/PMN aggregation, indicating that PSGL-1 was the major tethering ligand for P-selectin in this experimental system. Moreover, engagement of PSGL-1 with a nonadhesion blocking antibody triggered β2-integrin–dependent genistein-sensitive aggregation as well as tyrosine phosphorylation in PMN. This study shows that binding of P-selectin to PSGL-1 triggers tyrosine kinase–dependent mechanisms that lead to CD11b/CD18 activation in PMN. The availability of the β2-integrin to engage with its ligands on the neighboring cells is necessary for the tyrosine phosphorylation of P∼110.

Platelet/Polymorphonuclear Leukocyte Interaction: P-Selectin Triggers Protein-Tyrosine Phosphorylation–Dependent CD11b/CD18 Adhesion: Role of PSGL-1 as a Signaling Molecule

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 876-885 ◽  
Author(s):  
Virgilio Evangelista ◽  
Stefano Manarini ◽  
Rita Sideri ◽  
Serenella Rotondo ◽  
Nicola Martelli ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinase Inhibitors ◽  
Polymorphonuclear Leukocyte ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chinese Hamster ◽  
Mixed Cell ◽  
Β2 Integrin ◽  
Activated Platelets

Abstract Polymorphonuclear leukocyte (PMN) adhesion to activated platelets is important for the recruitment of PMN at sites of vascular damage and thrombus formation. We have recently shown that binding of activated platelets to PMN in mixed cell suspensions under shear involves P-selectin and the activated β2-integrin CD11b/CD18. Integrin activation required signaling mechanisms that were sensitive to tyrosine kinase inhibitors.1 Here we show that mixing activated, paraformaldehyde (PFA)-fixed platelets with PMNs under shear conditions leads to rapid and fully reversible tyrosine phosphorylation of a prominent protein of 110 kD (P∼110). Phosphorylation was both Ca2+ and Mg2+ dependent and was blocked by antibodies against P-selectin or CD11b/CD18, suggesting that both adhesion molecules need to engage with their respective ligands to trigger phosphorylation of P∼110. The inhibition of P∼110 phosphorylation by tyrosine kinase inhibitors correlates with the inhibition of platelet/PMN aggregation. Similar effects were observed when platelets were substituted by P-selectin–transfected Chinese hamster ovary (CHO-P) cells or when PMN were stimulated with P-selectin–IgG fusion protein. CHO-P/PMN mixed-cell aggregation and P-selectin–IgG–triggered PMN/PMN aggregation as well as P∼110 phosphorylation were all blocked by antibodies against P-selectin or CD18. In each case PMN adhesion was sensitive to the tyrosine kinase inhibitor genistein. The antibody PL-1 against P-selectin glycoprotein ligand-1 (PSGL-1) blocked platelet/PMN aggregation, indicating that PSGL-1 was the major tethering ligand for P-selectin in this experimental system. Moreover, engagement of PSGL-1 with a nonadhesion blocking antibody triggered β2-integrin–dependent genistein-sensitive aggregation as well as tyrosine phosphorylation in PMN. This study shows that binding of P-selectin to PSGL-1 triggers tyrosine kinase–dependent mechanisms that lead to CD11b/CD18 activation in PMN. The availability of the β2-integrin to engage with its ligands on the neighboring cells is necessary for the tyrosine phosphorylation of P∼110.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

The patient with renal cell cancer

2015 ◽  
Author(s):  
Tim Eisen
Keyword(s):  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cancer ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cell Cancer

Renal cancer is the commonest malignancy of the kidney and worldwide, accounts for between 2% and 3% of the total cancer burden. The mainstay of curative treatment remains surgery. There have been significant advances in surgical technique, the most important ones being nephron-sparing surgery and laparoscopic nephrectomy. The medical treatment of advanced renal cell cancer has only improved markedly in the last decade with the development of antiangiogenic tyrosine-kinase inhibitors, inhibitors of mammalian target of rapamycin, and a diminished role for immunotherapy.Tyrosine-kinase inhibitor therapy results in reduction of tumour volume in around three-quarters of patients and doubles progression-free survival, but treatment is not curative. The management of side effects in patients on maintenance tyrosine-kinase inhibitors has improved in the last 3 years, although still presents difficulties which have to be actively considered.The molecular biology of renal cell carcinoma is better understood than for the majority of solid tumours. The commonest form of renal cancer, clear-cell carcinoma of the kidney, is strongly associated with mutations in the von Hippel–Lindau gene and more recently with chromatin-remodelling genes such as PBRM1. These genetic abnormalities lead to a loss of control of angiogenesis and uncontrolled proliferation of tumour cells. There is a very wide spectrum of tumour behaviour from the extremely indolent to the terribly aggressive. It is not currently known what accounts for this disparity in tumour behaviour.A number of outstanding questions are being addressed in scientific and clinical studies such as a clearer understanding of prognostic and predictive molecular biomarkers, the role of adjuvant therapy, the role of surgery in the presence of metastatic disease, how best to use our existing agents, and investigation of novel targets and therapeutic agents, especially novel immunotherapies.

Role for tyrosine kinases in carbachol-regulated Ca entry into colonic epithelial cells

1995 ◽  
Vol 268 (1) ◽  
pp. C154-C161 ◽  
Author(s):  
G. Bischof ◽  
B. Illek ◽  
W. W. Reenstra ◽  
T. E. Machen
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Divalent Cations ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Colonic Epithelial Cells

We studied a possible role of tyrosine kinases in the regulation of Ca entry into colonic epithelial cells HT-29/B6 using digital image processing of fura 2 fluorescence. Both carbachol and thapsigargin increased Ca entry to a similar extent and Ca influx was reduced by the tyrosine kinase inhibitor genistein (50 microM). Further experiments were performed in solutions containing 95 mM K to depolarize the membrane potential, and the effects of different inhibitors on influx of Ca, Mn, and Ba were compared. Genistein, but not the inactive analogue daidzein nor the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2- methylpiperazine, decreased entry of all three divalent cations by 47-59%. In high-K solutions, carbachol or thapsigargin both caused intracellular Ca to increase to a plateau of 223 +/- 19 nM. This plateau was reduced by the tyrosine kinase inhibitors genistein (to 95 +/- 8 nM), lavendustin A (to 155 +/- 17 nM), and methyl-2,5-dihydroxycinnamate (to 39 +/- 3 nM). Orthovanadate, a protein tyrosine phosphatase inhibitor, prevented the inhibitory effect of genistein. Ca pumping was unaffected by genistein. Carbachol increased tyrosine phosphorylation (immunoblots with anti-phosphotyrosine antibodies) of 110-, 75-, and 70-kDa proteins, and this phosphorylation was inhibited by genistein. We conclude that carbachol and thapsigargin increase Ca entry, and tyrosine phosphorylation of some key proteins may be important for regulating this pathway.

scholarly journals Krónikus myeloid leukaemia miatt 2003 és 2019 között a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján kezelt betegek adatainak elemzése

2021 ◽  
Vol 162 (32) ◽  
pp. 1297-1302
Author(s):  
Júlia Weisinger ◽  
Ilona Tárkányi ◽  
Eid Hanna ◽  
Ágnes Kárpáti ◽  
Zsolt Nagy ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Treatment Change

Összefoglaló. Bevezetés: A krónikus myeloid leukaemia a diagnosztika fejlődésének és a tirozin-kináz-gátlók bevezetésének köszönhetően az elmúlt évtizedekben kiváló prognózisú betegséggé vált. Célkitűzés: A betegséggel kapcsolatos ismereteink nagy része klinikai vizsgálatokból származik, emiatt kiemelt szerepük van a nem szelektált beteganyagon végzett elemzéseknek. Módszer: Retrospektív elemzésünkben a Semmelweis Egyetem Belgyógyászati és Onkológiai Klinikáján 2003 és 2019 között tirozin-kináz-gátló kezelésben részesült betegek adatait tekintettük át. Eredmények: Klinikánkon összesen 88 beteg részesült terápiában, közülük 73 beteg az analízis időpontjában is kezelés alatt állt. A betegek 5 éves össztúlélése 86%, 5 éves progressziómentes túlélése 70% volt. 9 beteg halt meg, közülük 2 betegnél a halál oka a progrediáló alapbetegség volt. 38 betegnél volt szükség az első vonalban terápiaváltásra, a váltás oka akkor elsősorban az elégtelen terápiás válasz volt. A későbbi terápiaváltásokra elsősorban intolerancia miatt került sor. Az első vonalban a betegek több mint fele major molekuláris választ ért el, a jelenlegi kezelés mellett a betegek 85%-ánál major molekuláris választ detektáltunk. Megbeszélés: Adataink alapján az intézményünkben kezelt betegek túlélése és a betegek által elért terápiás válasz megfelel a nemzetközi adatoknak. Következtetés: Mivel nem válogatott beteganyagról van szó, a kapott eredmények pontosabb képet adhatnak a krónikus myeloid leukaemia tirozin-kináz-gátlóval történt kezelésének eredményeiről. Orv Hetil. 2021; 162(32): 1297–1302. Summary. Introduction: As a result of advances in diagnostic techniques and the introduction of tyrosine kinase inhibitors, the prognosis of chronic myeloid leukemia has improved over the last decades. Objective: Most of our knowledge about chronic myeloid leukemia results from clinical trials, therefore data derived from non-selected patient population is substantial. Method: Data of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors at the Department of Internal Medicine and Oncology, Semmelweis University, between 2003 and 2019 were analysed retrospectively. Results: 88 patients received treatment, 73 patients were on therapy at the time of the analysis. Overall survival at 5 years was 86%, progression-free survival at 5 years was 70%. 9 patients died, 2 of them due to progressive disease. 38 patients needed 2nd line therapy, the main reason of treatment change was failure of therapy. Subsequent treatment modifications were conducted mostly because of intolerance. More than half of the patients on 1st line treatment reached major molecular response and 85% of the patients on treatment at the end of the analysis are in major molecular response. Discussion: Based on our data, survival and therapeutic response of patients in our center are similar to the international results. Conclusion: This analysis provides real-world data about treatment results of chronic myeloid leukemia in the tyrosine kinase inhibitor era. Orv Hetil. 2021; 162(32): 1297–1302.

scholarly journals Individualization of Drug Therapy Mode in a Patient with Disseminated Form of GIST by Determining Active Metabolites of the Drug (Tyrosine Kinase Inhibitor) in Blood Plasma

2019 ◽  
Vol 2 (17) ◽  
pp. 38-42
Author(s):  
S. T. Adleyba ◽  
L. M. Kogonia ◽  
L. E. Gurevich ◽  
A. V. Sidorov
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Tyrosine Kinase ◽  
Blood Plasma ◽  
Tyrosine Kinase Inhibitors ◽  
High Performance ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Response To Therapy ◽  
Active Metabolites

An own experience of effective treatment of a patient with a disseminated form of gastrointestinal stromal tumor (GIST) with a preparation from the group of tyrosine kinase inhibitors (imatinib) is presented.Relevance. Therapy of gastrointestinal stromal tumors is still a complex problem of modern oncology. Since 2001, a breakthrough has occurred in the treatment of patients with GISTO due to the successful use of a targeted drug from the group of tyrosine kinase inhibitors — imatinib, which is effective in the first line of inoperable and / or metastatic GISTs, and is also used for the neoadjuvant, adjuvant therapy of localized GISTs. The lack of response to therapy and, consequently, the progression of the disease, may be associated with a decrease in the therapeutic concentration of imatinib in the blood plasma. Determining the concentration of active metabolites of imatinib in the serum allows timely identification of potential causes of insufficient response to therapy and individual correction of the dose of the drug.Materials and methods. In order to determine the significance of the correlation between increasing / decreasing the dose of imatinib and achieving a therapeutic response, we used a laboratory method of high performance liquid chromatography to determine the concentration of imatinib in serum.Conclusion. Determination of the reduced concentration of active metabolites of imatinib in the blood plasma by high performance liquid chromatography with the detection of tandem mass spectrometry in a patient with disseminated form of GIST allowed to correct the dose of the drug and achieve a positive effect.

scholarly journals Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the beta 2 integrin CD11b/CD18

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4183-4194 ◽  
Author(s):  
V Evangelista ◽  
S Manarini ◽  
S Rotondo ◽  
N Martelli ◽  
R Polischuk ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Inhibitory Antibody ◽  
Mixed Cell ◽  
Platelet Surface ◽  
Kinase Activation ◽  
Dynamic Conditions ◽  
Activated Platelets ◽  
Beta 2 ◽  
Adhesion Of Platelets

Adhesion between platelets and polymorphonuclear leukocytes (PMN) is a key event in thrombosis and inflammation. Double color fluorescence- activated cell sorter (FACS) analysis was used to determine the extent and kinetics of adhesion of thrombin-activated platelets to resting or activated PMN when mixed cell populations were incubated in dynamic conditions. Activated platelets bound very rapidly to PMN. Mixed cell conjugates reached a maximum at 1 minute and were reversible within 10 minutes. Platelet/PMN adhesion required both Ca2+ and Mg2+ and was markedly increased by the presence of Mn2+. The latter made mixed cell conjugates stable up to 10 minutes. Adhesion of platelets required metabolic activity of PMN and was abolished by tyrosine kinase inhibitors. Furthermore, adhesion of platelets to PMN resulted in binding of a monoclonal antibody (MoAb 24) known as beta 2 integrins “activation reporter.” When PMN were activated by exogenous stimuli, the adhesion of platelets was markedly increased: fMLP induced a rapid and transient effect, while PMA resulted in a slower, but stable, increase in mixed conjugates formation. The hypothesis that activated PMN beta 2 integrins are able to bind a counter-receptor on platelets was directly demonstrated by the increase of mixed cell conjugates following PMN treatment with KIM127 and KIM185, two anti-CD18 antibodies able to induce the active conformation of beta 2 integrins. Consistently, two other anti-CD18, as well as an anti-CD11b inhibitory antibody abolished platelet/PMN adhesion. PMN beta 2 integrin activation was not the only mechanism for activated platelet/PMN adhesion to occur: indeed, this phenomenon could also be inhibited by two anti-P-selectin antibodies. Resting platelets did not adhere to resting PMN, but markedly adhered to fMLP-or PMA-activated PMN. Resting platelet/fMLP-activated PMN adhesion was abolished by anti-CD18 antibodies, but not by anti-P-selectin antibodies. In conclusion, activated platelet/PMN interaction can be modeled as an adhesion cascade involving a P-selectin-dependent recognition step and a functional signal. The latter proceeds through tyrosine kinase activation and enables a beta 2 integrin-dependent adhesion to a not yet identified counter-receptor constitutively expressed on platelet surface.

scholarly journals Use of tyrosine kinase inhibitor by patients with chronic myeloid leukemia at a public hematology institution in the state of Amazonas, Brazil

2020 ◽  
Vol 11 (4) ◽  
pp. 510
Author(s):  
Andreia D. MENEZES ◽  
Nelson A. FRAIJI
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cross Sectional Study ◽  
Chi Square ◽  
Cross Sectional ◽  
The Right

Objectives: To evaluate the conditions of use of tyrosine kinase inhibitors and adherence by patients with chronic myeloid leukemia treated at a public hematology institution. Methods: This was an observational and cross-sectional study carried out from December 2015 to April 2016. Data collection was carried out through interviews with standardized questionnaires that assessed the socioeconomic and demographic profile, drug therapy and by the Morisky-Green test that assessed the green adherence. Patients over 18 years old who had been using one of the tyrosine kinase inhibitors for more than one month were included; imatinib, dasatinib or nilotinib and who signed the informed consert form, agreement to participate in study. Descriptive statistical analysis and chi-square test with Yates correction were performed. Results: 63 patients were interviewed, with a mean age of 50 years with a standard deviation of 15.95. being 60% men. As for knowledge about the aspects related to the use of inhibitors: 95.2% took at the right time, 93.7% did not use other medications concomitantly, 63.5% kept it in an appropriate place and 97% of the patients received prior guidance from the doctor about the use. As for information about treatment, 90.5% knew the purpose of taking the medication, 60% did not know the time of use, 83% did not know what would happen if they stopped taking it and 73% believed they could stop the treatment at some point. Adherence to treatment was identified 46% of patients. Conclusion: No statistically significant differences were found between having or not adherence, when compared with the studied variables.

Tyrosine kinase regulates epithelial sodium transport in A6 cells

1993 ◽  
Vol 264 (1) ◽  
pp. C246-C250 ◽  
Author(s):  
P. S. Matsumoto ◽  
A. Ohara ◽  
P. Duchatelle ◽  
D. C. Eaton
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Na Transport ◽  
Tyrosine Kinase Activity ◽  
Open Probability ◽  
Cyclic Monophosphate ◽  
Tyrphostin 23

Insulin increases epithelial Na+ reabsorption, and many of its actions involve tyrosine kinase. We used tyrosine kinase inhibitors to examine the role of tyrosine kinase in the action of insulin. Pretreatment of Na+ transporting cells with tyrosine kinase inhibitors attenuates the subsequent action of insulin, suggesting that the action of insulin on epithelial Na+ transport involves tyrosine kinase activity. In addition to their effect on insulin-induced Na+ transport, the tyrosine kinase inhibitors also significantly reduce Na+ transport in Na(+)-transporting epithelial cells, suggesting that there is a significant tonic tyrosine kinase activity that modulates epithelial Na+ transport. Using patch-clamp methods, we found that one inhibitor, genistein, reduces the number of active Na+ channels in cell-attached patches without significantly affecting the open probability of any remaining channels. The effects of the tyrosine kinase inhibitors are not due to inhibition of protein kinase A (PKA), since H89, a PKA inhibitor, does not affect Na+ transport of control cells (as the tyrosine kinase inhibitors do), and the tyrosine kinase inhibitor, genistein or tyrphostin 23, does not alter the stimulation of ion transport by 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, a membrane-permeable adenosine 3',5'-cyclic monophosphate analogue (as H89 does).

Sign in / Sign up

Export Citation Format

Share Document