Coronary arteriolar flow-induced vasodilation signals through tyrosine kinase

1996 ◽  
Vol 270 (6) ◽  
pp. H1878-H1884 ◽  
Author(s):  
J. M. Muller ◽  
M. J. Davis ◽  
W. M. Chilian
Keyword(s):  
Substance P ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Fluorescein Isothiocyanate ◽  
Intraluminal Pressure ◽  
Kinase Activation ◽  
Genistein Treatment ◽  
Dependent Flow ◽  
Coronary Arterioles

Coronary arterioles demonstrate flow-dependent vasodilation that is mediated by endothelial release of nitric oxide. The signaling mechanisms for this response remain unknown. Because tyrosine kinases are an enzyme family linked to many signaling pathways, including some for mechanosensitive transduction, we hypothesized that tyrosine kinase activation is a critical step in flow-induced vasodilation. To test this hypothesis, coronary arterioles were isolated, cannulated with micropipettes, and perfused by two independent reservoir systems. Intraluminal pressure was set at 60 cmH2O, and flow was generated by changing the heights of the reservoirs in equal and opposite directions, thus establishing a pressure difference across the arteriole without altering intraluminal pressure. Vasodilatory responses to intraluminal flow and substance P (1 x 10(-12) to 1 x 10(-7) M) were evaluated before and after intraluminal application of the tyrosine kinase inhibitors genistein (5 microM) and piceatannol (10 microM). Exposure to these inhibitors did not alter spontaneous tone. Substance P caused dose-dependent vasodilation that was not affected by genistein or piceatannol. Increases in intraluminal flow (generated by pressure differences ranging from 4 to 60 cmH2O) elicited graded increases in diameter. Both genistein and piceatannol inhibited the vasodilatory responses to flow. Treatment with daidzein, an inactive analogue of genistein, had no effect on either the flow-induced responses or substance P-induced vasodilation. To further confirm that tyrosine kinase activation is involved in flow-induced vasodilation, vessels were exposed to flow in the absence or presence of genistein and subsequently stained with a fluorescein isothiocyanate-labeled phosphotyrosine antibody. Exposure to flow significantly increased fluorescence of endothelial cells. Genistein treatment reversed the flow-induced increase in tyrosine phosphorylation. These results indicate that endothelium-dependent, flow-induced vasodilation in isolated porcine coronary arterioles is accompanied by an increase in tyrosine kinase activity. We conclude that endothelium-dependent, nitroxidergic, flow-induced vasodilation is mediated, at least in part, by a signaling pathway involving a tyrosine kinase.

scholarly journals Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

2021 ◽  
Vol 14 (7) ◽  
pp. 626
Author(s):  
Julie Bolcaen ◽  
Shankari Nair ◽  
Cathryn H. S. Driver ◽  
Tebatso M. G. Boshomane ◽  
Thomas Ebenhan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Radionuclide Therapy ◽  
Kinase Inhibitors ◽  
Nuclear Imaging ◽  
Therapy Resistance ◽  
Targeted Radionuclide Therapy ◽  
Therapy Strategy ◽  
Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

Oncostatin M regulates endothelin-1 production in human endothelial cells

1998 ◽  
Vol 275 (2) ◽  
pp. H662-H667 ◽  
Author(s):  
Outi Saijonmaa ◽  
Tuulikki Nyman ◽  
Päivi Pacek ◽  
Frej Fyhrquist
Keyword(s):  
Endothelial Cells ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Oncostatin M ◽  
Human Umbilical Cord ◽  
Kinase Activation ◽  
Endothelin 1 ◽  
Umbilical Cord Vein ◽  
Pkc Activation ◽  
Human Umbilical Cord Vein

The effect of the macrophage- and T-lymphocyte-derived cytokine oncostatin M (OSM) on endothelin-1 (ET-1) production in cultured human umbilical cord vein endothelial cells (HUVEC) was studied. OSM (2.5–10 ng/ml) stimulated ET-1 production and the expression of preproendothelin-1 mRNA. The stimulatory effect of OSM was reversed by anti-interleukin (IL)-6 IgG (33 μg/ml). IL-6 (10 ng/ml) was shown to stimulate ET-1 production. The tyrosine kinase inhibitors herbimycin (250–500 ng/ml) and genistein (1–4 μg/ml) suppressed basal ET-1 production and reversed the stimulatory effect of OSM, whereas daidzein (1–8 μg/ml), a less active analog of genistein, had no effect on basal ET-1 production and only partly reversed the stimulatory effect of OSM. The phorbol ester phorbol 12-myristate 13-acetate (PMA) inhibited ET-1 production. Downregulation of protein kinase C (PKC) with PMA (1 μM) preincubation potentiated OSM-induced ET-1 production. In summary, OSM stimulated ET-1 production in cultured HUVEC. The stimulation was probably mediated by IL-6. Furthermore, the present data suggest that tyrosine kinase activation was involved in ET-1 stimulation and that PKC activation leads to suppression of basal and OSM-stimulated ET-1 production.

scholarly journals Transmission of growth cone traction force through apCAM–cytoskeletal linkages is regulated by Src family tyrosine kinase activity

2001 ◽  
Vol 155 (3) ◽  
pp. 427-438 ◽  
Author(s):  
Daniel M. Suter ◽  
Paul Forscher
Keyword(s):  
Tyrosine Kinase ◽  
Growth Cone ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Traction Force ◽  
Tyrosine Kinase Activity ◽  
Cellular Mechanisms ◽  
Traction Forces ◽  
Kinase Activation ◽  
Neuronal Growth Cone

Tyrosine kinase activity is known to be important in neuronal growth cone guidance. However, underlying cellular mechanisms are largely unclear. Here, we report how Src family tyrosine kinase activity controls apCAM-mediated growth cone steering by regulating the transmission of traction forces through receptor–cytoskeletal linkages. Increased levels of tyrosine phosphorylation were detected at sites where beads coated with apCAM ligands were physically restrained to induce growth cone steering, but not at unrestrained bead binding sites. Interestingly, the rate and level of phosphotyrosine buildup near restrained beads were decreased by the myosin inhibitor 2,3-butanedione-2-monoxime, suggesting that tension promotes tyrosine kinase activation. While not affecting retrograde F-actin flow rates, genistein and the Src family selective tyrosine kinase inhibitors PP1 and PP2 strongly reduced the growth cone's ability to apply traction forces through apCAM–cytoskeletal linkages, assessed using the restrained bead interaction assay. Furthermore, increased levels of an activated Src family kinase were detected at restrained bead sites during growth cone steering events. Our results suggest a mechanism by which growth cones select pathways by sampling both the molecular nature of the substrate and its ability to withstand the application of traction forces.

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 Combating Acquired Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2015 ◽  
pp. e165-e173 ◽  
Author(s):  
Christine M. Lovly
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Initial Response ◽  
In Vitro Models ◽  
Tumor Biopsy

The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine. Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.

TEL/PDGFβR Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1707-1714 ◽  
Author(s):  
Michael H. Tomasson ◽  
Ifor R. Williams ◽  
Robert Hasserjian ◽  
Chirayu Udomsakdi ◽  
Shannon M. McGrath ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Transgenic Animals ◽  
Myeloid Lineage ◽  
Protein Tyrosine

Abstract The TEL/PDGFβR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFβR is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties of TEL/PDGFβR in vivo, and to analyze the basis for myeloid lineage specificity in humans, we constructed transgenic mice with TEL/PDGFβR expression driven by a lymphoid-specific immunoglobulin enhancer-promoter cassette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGFβR is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted to the myeloid lineage. Treatment of TEL/PDGFβR transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGFβR (CGP57148) resulted in suppression of disease and a prolongation of survival. A therapeutic benefit was apparent both in animals treated before the development of overt clonal disease and in animals transplanted with clonal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase–mediated malignancies both early in the course of disease and after the development of additional transforming mutations.

Activation of tyrosine kinases in H2O2-induced contraction in pulmonary artery

1997 ◽  
Vol 272 (6) ◽  
pp. H2686-H2692 ◽  
Author(s):  
N. Jin ◽  
R. A. Rhoades
Keyword(s):  
Smooth Muscle ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Pulmonary Arteries ◽  
Smooth Muscle Contraction ◽  
Muscle Dysfunction ◽  
Calmodulin Antagonist ◽  
Smooth Muscle Dysfunction

Hydrogen peroxide (H2O2) is an important reactive oxygen species implicated in lung vascular constriction and injury. The purpose of this study was to investigate the role of tyrosine kinases in H2O2-induced vascular contraction and dysfunction. In our study, H2O2 (200 microM) caused an initial transient contraction followed by a strong, sustained contraction in isolated rat pulmonary arteries. Genistein, a tyrosine kinase inhibitor, attenuated both the initial and the sustained contractions. Aminogenistein and tyrphostin 51, specific inhibitors of tyrosine kinases, had the same effects as genistein. Exposure of pulmonary arteries to H2O2 for 1 h caused a significant reduction in the contractile response to KCl or phenylephrine and in the vasodilatory response to acetylcholine (smooth muscle dysfunction). Although tyrosine kinase inhibitors significantly blocked contractions induced by H2O2, pretreatment of pulmonary arteries with these inhibitors before H2O2 exposure did not prevent the decreases in responses to KCl, phenylephrine, or acetylcholine. Removal of extracellular Ca2+ and depletion of intracellular Ca2+ pools by ryanodine or thapsigargin did not inhibit the initial and sustained contractions in response to H2O2. W-7, a calmodulin antagonist, or ML-9, a myosin light chain kinase inhibitor, significantly inhibited the sustained contractions but did not prevent smooth muscle dysfunction induced by H2O2. These data show that 1) exposure to H2O2 causes smooth muscle contractions and dysfunction in isolated pulmonary arteries and 2) activation of tyrosine kinases mediates H2O2-induced contractions; however, tyrosine kinases do not appear to be involved in H2O2-induced inhibition of arterial responses to vasoactive substances. These data suggest that different signaling pathways and mechanisms are involved in H2O2-induced smooth muscle contraction and dysfunction.

Thrombin Mediated Tyrosine Phosphorylation of PKCδ in Human Platelets Occurs in a Calcium- and Src Family Tyrosine Kinase- Dependent Manner.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3541-3541
Author(s):  
Swaminathan Murugappan ◽  
Haripriya Shankar ◽  
Satya Kunapuli
Keyword(s):  
Tyrosine Kinase ◽  
Intracellular Calcium ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Human Platelets ◽  
Dependent Manner ◽  
Protein Signaling ◽  
Glycoprotein Vi ◽  
Pkc Isoforms

Abstract Protein kinase C (PKC)-δ is a novel PKC that has been shown to be tyrosine phosphorylated upon stimulation with agonists in platelets. Tyrosine phosphorylation of PKCδ has been shown to occur in a Fyn-dependent manner downstream of glycoprotein VI (GPVI) signaling in platelets. Although thrombin causes tyrosine phosphorylation of PKCδ in platelets, the mechanism of this event is not elucidated. In this study, we investigated whether G-protein signaling pathways utilize similar pathways as GPVI in tyrosine phosphorylation of PKCδ. Protease activated receptor (PAR) -1 selective peptide, SFLLRN and PAR - 4 selective peptide, AYPGKF caused a time- and concentration-dependent increase in tyrosine phosphorylation of PKCδ in human platelets. However, AYPGKF failed to cause tyrosine phosphorylation of PKCδ in Gq-deficient mouse platelets. Both U73122, a phospholipase C (PLC) inhibitor, and dimethyl-BAPTA, an intracellular calcium chelator, inhibited the tyrosine phosphorylation of PKCδ downstream of the PAR activation suggesting a role for Gq/PLC pathways and intracellular calcium in mediating this event. Inhibition of PKC isoforms using GF109203X potentiated the tyrosine phosphorylation of PKCδ. The Src family tyrosine kinase inhibitors, PP1 and PP2 inhibited the tyrosine phosphorylation of PKCδ suggesting a role for Src family tyrosine kinase members in this event. We also found that both Lyn and Src are physically associated with PKCδ in a constitutive manner in platelets. Finally we found that there was a time-dependent activation of Src following activation of platelets with thrombin. Thus, the precomplexed Src and Lyn tyrosine kinases get activated following PAR stimulation resulting in the tyrosine phosphorylation of PKCδ. All these data indicate that tyrosine phosphorylation of PKCδ downstream of thrombin occurs in a calcium- and Src-family kinase dependent manner in human platelets.

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