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.

Communication between tyrosine kinase pathway and myosin light chain kinase pathway in smooth muscle

1996 ◽  
Vol 271 (4) ◽  
pp. H1348-H1355 ◽  
Author(s):  
N. Jin ◽  
R. A. Siddiqui ◽  
D. English ◽  
R. A. Rhoades
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Light Chain ◽  
Tyrosine Kinases ◽  
Myosin Light Chain ◽  
Smooth Muscle Contraction ◽  
Myosin Light Chain Phosphorylation ◽  
Kinase Pathway

Two separate signal transduction pathways exist in vascular smooth muscle: one for cell growth, proliferation, and differentiation and the other for contraction. Although activation of protein tyrosine kinases is intimately involved in the signaling pathway that induces cell growth, proliferation, and differentiation, activation of myosin light chain kinase (MLCK) is an important step in the pathway leading to smooth muscle contraction. Indirect evidence suggests that “cross talk” exists between these two signaling pathways, but the common intermediates are not well defined. The purpose of this study was to determine whether a vasoconstrictor and a mitogen initiate crossover signaling between the tyrosine kinase pathway and the MLCK pathway in vascular smooth muscle. Rat aorta and pulmonary arteries were isolated and stimulated with either fetal calf serum (FCS) or phenylephrine in the presence or absence of a tyrosine kinase inhibitor (genistein) or tyrosine phosphatase inhibitor [sodium o-vanadate (Na3 VO4)]. Isometric force was recorded as a function of time; myosin light chain phosphorylation, protein tyrosine phosphorylation, and mitogen-activated protein kinase (MAPK) mobility were determined by immunoblotting. The results demonstrate that FCS, which contains a variety of growth factors known to activate tyrosine kinases, induced myosin light chain phosphorylation and contraction in vascular smooth muscle. Phenylephrine, a vasoconstrictor known to activate MLCK, induced tyrosine phosphorylation of a 42-kDa protein identified as MAPK. Tyrosine phosphorylation of this protein was inhibited by genistein and enhanced by vanadate. Genistein significantly inhibited both serum- and phenylephrine-induced myosin light chain phosphorylation as well as the serum- and phenylephrine-induced force generation, whereas vanadate enhanced these responses. These data demonstrate interrelationship between activation of the tyrosine kinase pathway and the MLCK pathway in vascular smooth muscle. These interactions may influence smooth muscle contraction and be important in the regulation of smooth muscle cell proliferation.

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.

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.

Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport?

2006 ◽  
Vol 290 (1) ◽  
pp. E123-E128 ◽  
Author(s):  
David C. Wright ◽  
Paige C. Geiger ◽  
Dong-Ho Han ◽  
John O. Holloszy
Keyword(s):  
Protein Kinase ◽  
Cell Surface ◽  
Tyrosine Kinase ◽  
Glucose Transport ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Muscle Contractions ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein

Muscle contractions and insulin stimulate glucose transport into muscle by separate pathways. The contraction-mediated increase in glucose transport is mediated by two mechanisms, one involves the activation of 5′-AMP-activated protein kinase (AMPK) and the other involves the activation of calcium/calmodulin-dependent protein kinase II (CAMKII). The steps leading from the activation of AMPK and CAMKII to the translocation of GLUT4 to the cell surface have not been identified. Studies with the use of the tyrosine kinase inhibitor genistein suggest that one or more tyrosine kinases could be involved in contraction-stimulated glucose transport. The purpose of the present study was to determine the involvement of tyrosine kinases in contraction-stimulated glucose transport in rat soleus and epitrochlearis muscles. Contraction-stimulated glucose transport was completely prevented by pretreatment with genistein (100 μM) and the related compound butein (100 μM). However, the structurally distinct tyrosine kinase inhibitors 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4-d]pyridine and herbimycin did not reduce contraction-stimulated glucose transport. Furthermore, genistein and butein inhibited glucose transport even when muscles were exposed to these compounds after being stimulated to contract. Muscle contractions did not result in increases in tyrosine phosphorylation of proteins such as proline-rich tyrosine kinase and SRC. These results provide evidence that tyrosine kinases do not mediate contraction-stimulated glucose transport and that the inhibitory effects of genistein on glucose transport result from direct inhibition of the glucose transporters at the cell surface.

Attenuation of endothelin-1-induced calcium response by tyrosine kinase inhibitors in vascular smooth muscle cells

1996 ◽  
Vol 270 (6) ◽  
pp. C1825-C1833 ◽  
Author(s):  
C. Y. Liu ◽  
M. Sturek
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Tyrosine Kinase ◽  
Smooth Muscle Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Muscle Cells ◽  
Endothelin 1 ◽  
Fura 2

Although tyrosine kinases play an important role in cell growth and have been implicated in regulation of smooth muscle contraction, their role in agonist-induced myoplasmic Ca2+ responses is unclear. We examined effects of the tyrosine kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) on the endothelin-1 (ET-1)-induced Ca2+ response and determined underlying mechanisms for the effects. Freshly isolated smooth muscle cells from porcine coronary arteries were loaded with fura 2 ester, and myoplasmic free Ca2+ (Ca2+ (m)) concentration was estimated with fura 2 microfluorometry. Both genistein and MDHC inhibited the initial transient Cam2+ response to ET by 54 and 81%, respectively (P < 0.05), in the presence of extracellular Ca2+. Genistein also significantly delayed the Cam2+ response, with the latent period from ET-1 application to the beginning of the Cam2+ response being increased from 1.08 +/- 0.17 to 2.65 +/- 0.52 min (P < 0.05). In the absence of extracellular Ca2+, genistein inhibited the ET-1-induced Cam2+ response by 93% (P < 0.05). The Cam2+ responses to caffeine (5 mM) or inositol trisphosphate (IP3) applied intracellularly via a patch-clamp pipette were not affected by genistein. Both genistein and MDHC also abolished the sustained Cam2+ response to ET-1. However, the Cam2+ response to depolarization by 80 mM K+ was not inhibited by MDHC and only inhibited 22% by genistein (P < 0.05). These results indicate that 1) activation of tyrosine kinases is an important regulatory mechanism for the ET-1-induced Cam2+ response in vascular smooth muscle and 2) tyrosine kinases mediate ET-1-induced Ca2+ release with no direct effect on IP3-mediated Ca2+ release. Thus ET-1-mediated signaling upstream of IP3 interaction with the Ca2+ stores is regulated by tyrosine kinases.

scholarly journals Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1618
Author(s):  
Emilie Logie ◽  
Chandra S. Chirumamilla ◽  
Claudina Perez-Novo ◽  
Priyanka Shaw ◽  
Ken Declerck ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Affinity Purification ◽  
Therapy Resistance ◽  
Withaferin A ◽  
Major Barrier ◽  
Covalent Interaction

Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells’ uncontrolled growth. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to anticancer drugs. Often, this therapy resistance is associated with constitutive hyperactivation of tyrosine kinase signaling. Novel covalent kinase inhibitors, such as the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical withaferin A (WA), have, therefore, gained pharmaceutical interest. Remarkably, WA is more effective than IBR in killing BTK-overexpressing glucocorticoid (GC)-resistant MM1R cells. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. In contrast to IBR, WA was found to reverse BTK overexpression in GC-resistant MM1R cells. Furthermore, WA-induced cell death involves covalent cysteine targeting of Hinge-6 domain type tyrosine kinases of the kinase cysteinome classification, including inhibition of the hyperactivated BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal microscopy. Similarly, molecular modeling suggests WA preferably targets conserved cysteines in the Hinge-6 region of the kinase cysteinome classification, favoring inhibition of multiple B-cell receptors (BCR) family kinases. Altogether, we show that WA’s promiscuous inhibition of multiple BTK family tyrosine kinases represents a highly effective strategy to overcome GC-therapy resistance in MM.

scholarly journals Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles

2021 ◽  
Vol 22 (13) ◽  
pp. 6938
Author(s):  
You-Zhe Lin ◽  
Yi-Chun Shen ◽  
Wan-Rong Wu ◽  
Wei-Jan Wang ◽  
Yuan-Liang Wang ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cell Entry ◽  
Cell Surface Receptor ◽  
Renal Tubules ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.

scholarly journals Nilotinib-Associated Destructive Thyroiditis

2015 ◽  
Vol 2015 ◽  
pp. 1-3 ◽  
Author(s):  
Suhalia Bakerywala ◽  
Monica D. Schwarcz ◽  
Michael D. Goldberg ◽  
Guy Valiquette ◽  
Irene A. Weiss
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cellular Growth ◽  
Unusual Complication ◽  
Tyrosine Kinase Inhibitor Therapy

Protein tyrosine kinase inhibitors are currently an important drug class in the treatment of leukemia. They represent targeted cancer therapy and have become the treatment of choice in chronic myeloid leukemia. Tyrosine kinases are enzymes expressed in multiple tissues and are involved in several signaling pathways influencing cellular growth. Below we describe a patient who developed an unusual complication of tyrosine kinase inhibitor therapy: thyrotoxicosis due to destructive thyroiditis. We review the pathophysiology of tyrosine kinase inhibitor-induced thyroid dysfunction particularly with regard to new second-generation tyrosine kinase inhibitors.

scholarly journals Tyrosine Kinase Inhibitor Family of Drugs as Prospective Targeted Therapy for COVID-19 Based on In Silico And 3D-Human Vascular Lung Model Studies

2021 ◽  
Author(s):  
Shalini Saxena ◽  
Kranti Meher ◽  
Madhuri Rotella ◽  
Subhramanyam Vangala ◽  
Satish Chandran ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Lung Model ◽  
Common Mechanism ◽  
Model Studies ◽  
Chemical Structures

COVID-19 pandemic has ravaged the world and vaccines have been rapidly developed as preventive measures. But there is no target-based therapy which can be used if infection sets in. Remdesiver and dexamethasone were not designed to combat COVID-19 but are used clinically till better targeted therapies are available. Given this situation target based therapies that intervene in the disease pathway are urgently needed. Since COVID-19 genesis is driven by uncontrolled inflammation and thrombosis and protein kinases are critical in mounting this response, we explored if available tyrosine kinase inhibitors (TKI) can be used as intervention. We profiled four TKI namely Lapatinib, Dasatinib, Pazopanib and Sitravatinib which inhibit tyrosine kinases but are completely distinct in their chemical structures. We demonstrate using in silico and an in vitro 3D-human vascular lung model which profiles anti-inflammatory and anti-thrombogenic properties that all four TKI are active in varying degrees. Our findings that chemically different TKI which share kinase inhibition as the common mechanism of action are active, strongly indicates that it is a tyrosine kinase target-based activity and not off-target arbitrary effect. We propose that TKI, approved for human use and widely available, can be rapidly deployed as specific target-based therapy for COVID-19.

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

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.

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