scholarly journals Stable interaction between α5β1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1

2005 ◽  
Vol 170 (6) ◽  
pp. 993-1004 ◽  
Author(s):  
Ilaria Cascone ◽  
Lucia Napione ◽  
Fabrizio Maniero ◽  
Guido Serini ◽  
Federico Bussolino
Keyword(s):  
Tyrosine Kinase ◽  
Cross Talk ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor ◽  
Dynamic Interactions ◽  
Tie2 Receptor ◽  
Low Concentrations ◽  
Endothelial Cell Response ◽  
Blocking Antibodies

During angiogenic remodeling, Ang-1, the ligand of Tie2 tyrosine kinase, is involved in vessel sprouting and stabilization through unclear effects on nascent capillaries and mural cells. In our study, we hypothesized that the Ang-1/Tie2 system could cross-talk with integrins, and be influenced by the dynamic interactions between extracellular matrix and endothelial cells (ECs). Here, we show that α5β1 specifically sensitizes and modulates Tie2 receptor activation and signaling, allowing EC survival at low concentrations of Ang-1 and inducing persistent EC motility. Tie2 and α5β1 interact constitutively; α5β1 binding to fibronectin increases this association, whereas Ang-1 stimulation recruits p85 and FAK to this complex. Furthermore, we demonstrate that Ang-1 is able to mediate selectively α5β1 outside-in FAK phosphorylation. Thus, Ang-1 triggers signaling pathways through Tie2 and α5β1 receptors that could cross-talk when Tie2/α5β1 interaction occurs in ECs plated on fibronectin. By using blocking antibodies, we consistently found that α5β1, but not αvβ3 activation, is essential to Ang-1–dependent angiogenesis in vivo.

scholarly journals The product of a gas6 splice variant allows the release of the domain responsible for Axl tyrosine kinase receptor activation

FEBS Letters ◽  
1997 ◽  
Vol 415 (1) ◽  
pp. 59-63 ◽  
Author(s):  
Sandro Goruppi ◽  
Harvey Yamane ◽  
Paolo Marcandalli ◽  
Andy Garcia ◽  
Cris Clogston ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Splice Variant ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor

FLT-3 Activity and Its Response to Drugs Can Be Determined in AML Blast Cells by FLT-3 Phosphorylation Status Using Flow Cytometry.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2308-2308
Author(s):  
Tiziana Grafone ◽  
Michela Palmisano ◽  
Emanuela Ottaviani ◽  
Alberto Maria Martelli ◽  
Alessandra Cappellini ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Receptor Activation ◽  
Molecular Defects ◽  
Activating Mutation ◽  
Blast Cells ◽  
The Mean

Abstract One of the most common molecular defects identified in acute myeloid leukemia (AML) patients is an activating mutation of FLT3 tyrosine kinase. The identification of activated FLT3 as a contributor to the cause and progression of much leukemia has led to its consideration as a potential target for therapy. Since small molecule FLT3 kinase inhibitors are actually in clinical trials; a robust and standardized method for screening of FLT3 receptor activation is necessary. We evaluated the expression level of FLT3 receptor (CD135) by Facs analysis. We developed a flow cytometry method to measure FLT3 phosphorylation (P-FLT3) in samples with <10 (e)5 cells. The amount of P-FLT3 in the samples was determined as the mean fluorescence intensity (MFI). The P-FLT3 status of the treated samples was expressed as a percentage of the untreated control (100%). The method was first validated in FLT3 wild-type (HL-60) and mutant (MV4-11/ITD+) as well as FLT3 negative (K562) cell lines. The method also provides to be reproducible with samples AML from patients. Analysis was performed after exposure to drugs, in vitro and in vivo. In response to increasing drugs concentration (CEP-701 and SU11657) there was a linear reduction in P-FLT3. The results validate a rapid method to detect P-FLT3 protein at the single cell level by flow cytometry, and enable an accurate assessment of FLT3 kinase activity in blast cells in response to novel tyrosine kinase inhibitors.

scholarly journals Docking studies of Physalis peruviana ethanol extract using molegro virtual docker on insulin tyrosine kinase receptor as antidiabetic agent

2014 ◽  
Vol 3 (5) ◽  
pp. 265-269 ◽  
Author(s):  
Ayik Rosita Puspaningtyas
Keyword(s):  
Tyrosine Kinase ◽  
Ethanol Extract ◽  
Pharmaceutical Journal ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Tyrosine Kinase Receptor ◽  
Molegro Virtual Docker ◽  
Physalis Peruviana ◽  
Urban People

Physalis peruviana Linn in Indonesia was better known as ciplukan, based on information from urban people in Indonesia is as antidiabetic. In the previeous studies, the levels of blood glucose in animals experimental of Physalis peruviana quantified with glucometer and compared with oral antidiabetic drugs gliclazide, showed that Gliclazide was decrease more levels of glucose significantly than ethanol extract of Physalis peruviana. We have done molecular docking using Molegro Virtual Docker (MVD) on ethanol extract of Physalis peruviana and gliclazide to compare between in silico and in vivo studies. Based on studies before the main content of the ethanol extract of Physalis peruviana were withanolide, 4-OH-withanolide, and perulactone. In this study the results showed that gliclazide had been better bond in insulin tyrosine kinase receptor than main content of Physalis peruviana which can be seen from Moldock score 105.217 and Rerank score -68,2931 means that the energy was lower and more stable binding. Moldock Score of main content Physalis peruviana (withanolide, 4-OH-withanolide, and perulactone) were -93.5472; 70.5843; 88.7881, respectively. Rerank score of main content Physalis peruviana (withanolide, 4-OH-withanolide, and perulactone) were -61.5149; -67.5345; -65.7979, respectively. The hydrogen bonds of withanolide, 4-OH-withanolide, perulactone and gliclazide with amino acid of insulin tyrosine kinase receptor were Phe 1186 and Thr 1186. Finally, in the 3D MVD visualization between main content of ethanol extract of Physalis peruviana and gliclazide can be concluded that interaction of gliclazide was more harmonious than main content of ethanol extract Physalis peruviana.DOI: http://dx.doi.org/10.3329/icpj.v3i5.18534 International Current Pharmaceutical Journal, April 2014, 3(5): 265-269

scholarly journals The Tyrosine Kinase Receptor RET Interacts in Vivo with Aryl Hydrocarbon Receptor-Interacting Protein to Alter Survivin Availability

2009 ◽  
Vol 23 (6) ◽  
pp. 944-944
Author(s):  
Manuela Vargiolu ◽  
Daniela Fusco ◽  
Ivana Kurelac ◽  
Dietmar Dirnberger ◽  
Ralf Baumeister ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Aryl Hydrocarbon Receptor ◽  
Tyrosine Kinase Receptor ◽  
Interacting Protein ◽  
Aryl Hydrocarbon

scholarly journals Differential receptor tyrosine kinase phosphorylation in the uterus of rats following developmental exposure to tetrabromobisphenol A

2021 ◽  
Vol 5 ◽  
pp. 239784732110471
Author(s):  
Lysandra Castro ◽  
Jingli Liu ◽  
Linda Yu ◽  
Alanna D Burwell ◽  
Trey O Saddler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Early Life ◽  
Endometrial Adenocarcinoma ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Tetrabromobisphenol A ◽  
Tyrosine Kinase Receptor ◽  
Uterine Tumors

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that induces endometrial adenocarcinoma and other uterine tumors in Wistar Han rats; however, early molecular events or biomarkers of TBBPA exposure remain unknown. We investigated the effects of TBBPA on growth factor receptor activation [phospho-receptor tyrosine kinases (RTKs)] in uteri of rats following early-life exposures. Pregnant Wistar Han rats were exposed to TBBPA (0, 0.1, 25, and 250 mg/kg bw/day) via oral gavage on gestation day 6 through weaning of pups on postnatal day (PND) 21. Pups were exposed in utero, through lactation, and by daily gavage from PND 22 to PND 90. Uterine horns were collected (at PND 21, PND 33, and PND 90) and formalin-fixed or frozen for histologic, immunohistochemical, phospho-RTK arrays, or western blot analysis. At PND 21, the phospho-RTKs, fibroblast growth factor receptor 2 and 3 (FGFR2 and FGFR3), neurotrophic tyrosine kinase receptor type 3 (TRKC), and EPH receptor A1 (EPHA1) were significantly increased at different treatment concentrations. Several phospho-RTKs were also significantly overexpressed at PND 33 which included epithelial growth factor receptor (EGFR), FGFR2, FGFR3, FGFR4, insulin-like growth factor receptor 1 (IGF1R), insulin receptor (INSR), AXL receptor tyrosine kinase (AXL), MER proto-oncogene, tyrosine kinase (MERTK), platelet derived growth factor receptor alpha and beta (PDGFRA and PDGFRB), ret proto-oncogene (RET), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 and 2 (TIE1 and TIE2), TRKA, kinase insert domain receptor (KDR;VEGFR2), fms related receptor tyrosine kinase (FLT4; VEGFR3), and EPHA1 at different treatment concentrations. EGFR, a RTK overexpressed in endometrial cancer in women, remained significantly increased for all treatment groups at PND 90. Erb-B2 receptor tyrosine kinase 2 (ERBB2) and IGF1R were overexpressed at PND 33 and remained increased through PND 90, although ERBB2 was statistically significant at PND 90. The phospho-RTKs, FGFR3, AXL, TYRO3 protien tyrosine kinase (TYRO3; DTK), HGFR, TRKC, FLT1/VEGFR1, and EPHB2 and 4 were also statistically significant at PND 90 at different treatment doses. The downstream effector, phospho-MAPK44/42, was also increased in uteri of treated rats. Our findings show RTKs are dysregulated following early-life TBBPA exposures and their sustained activation may contribute to TBBPA-induced uterine tumors observed in rats later in life.

Abstract 253: The Tyrosine Kinase ErbB2 Inhibitor Lapatinib and the Anti-ErbB2 Antibody Trastuzumab Depress Cardiac Function Without Inducing Left Ventricular Dilation in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Carlo G Tocchetti ◽  
Carmela Coppola ◽  
Domenica Rea ◽  
Antonio Barbieri ◽  
Giuseppe Palma ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Systolic Dysfunction ◽  
Myocardial Strain ◽  
Kinase Domain ◽  
Left Ventricular ◽  
Tyrosine Kinase Receptor ◽  
Lv Function ◽  
Tyrosine Kinase Domain ◽  
Breast Cancers

Background: ErbB2, tyrosine kinase receptor of the EGFR family, overexpressed in about 25% of breast cancers, modulates development and function in the myocardium. Lapatinib (LAP) is a small molecule that inhibits ErbB2-tyrosine kinase domain. The few existing trials report it to be associated with a low risk of LV dysfunction (2%), while the prototypical antibody Trastuzumab (TRAS) increases the frequency of asymptomatic ejection fraction decrease by 3-18%, and the risk of heart failure by 2-4%. Here, we characterize our LAP murine cardiotoxicity model in vivo by echocardiography, comparing it to TRAS and doxorubicin (DOX) cardiotoxicities. Methods: LV end-diastolic and end-systolic diameters (LVEDD and LVESD) were assessed. LV function was measured with fractional shortening (FS) by M-mode echo, and with radial myocardial strain (%) with speckle tracking (ST) in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2 and 7 days of daily administration of LAP (100mg/kg/day orally), and in control mice. For comparison we used our well-established models with TRAS (2.25 mg/kg/day, ip), and DOX (2.17 mg/kg/day ip) as positive control. Results: FS was already reduced with DOX at 2 days: 52±.2%, p<.001 vs 60±.4% (sham), while LAP and TRAS decreased FS only at 7 days (56±2 and 49±1.5%, respectively, both p<.05 vs 60±.5% for sham). Interestingly, FS reduction with LAP was milder than with TRAS (p=.01). At 7 days, both LAP and TRAS only increased LVESD: 1.23±.07 and 1.49±.07mm, respectively, both p<.05 vs 1.1±.03mm (sham). On the other hand, at 7 days DOX induced LV dilation, with significant enlargement of both LVESD (1.55±.08mm) and LVEDD (3.04±.06mm; sham=2.81±.03mm), both p<.005. Importantly, from a diagnostic point of view, myocardial strain was reduced early at 2 days with LAP and TRAS, predicting cardiotoxicity: 34±7% for LAP, 44±7% for TRAS, both p<.05 vs sham (66±.6%). Conclusions: Differently from DOX, ErbB2 inhibition in mice does not produce LV dilation, but only decreases LV function. In particular, specifically targeting ErbB2-tyrosine kinase domain with LAP confers less cardiotoxicity than TRAS. Myocardial strain identifies LV systolic dysfunction earlier than conventional echo and can be a useful tool to predict ErbB2 inhibitors cardiotoxicity.

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Blood ◽  
2009 ◽  
Vol 114 (25) ◽  
pp. 5236-5244 ◽  
Author(s):  
Martina Tremmel ◽  
Alexandra Matzke ◽  
Imke Albrecht ◽  
Anna M. Laib ◽  
Vivienne Olaku ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Surface Protein ◽  
Receptor Activation ◽  
Tubule Formation ◽  
Kinase C ◽  
Promising Target ◽  
Hepatocyte Growth

Abstract A specific splice variant of the CD44 cell- surface protein family, CD44v6, has been shown to act as a coreceptor for the receptor tyrosine kinase c-Met on epithelial cells. Here we show that also on endothelial cells (ECs), the activity of c-Met is dependent on CD44v6. Furthermore, another receptor tyrosine kinase, VEGFR-2, is also regulated by CD44v6. The CD44v6 ectodomain and a small peptide mimicking a specific extracellular motif of CD44v6 or a CD44v6-specific antibody prevent CD44v6-mediated receptor activation. This indicates that the extracellular part of CD44v6 is required for interaction with c-Met or VEGFR-2. In the cytoplasm, signaling by activated c-Met and VEGFR-2 requires association of the CD44 carboxy-terminus with ezrin that couples CD44v6 to the cytoskeleton. CD44v6 controls EC migration, sprouting, and tubule formation induced by hepatocyte growth factor (HGF) or VEGF-A. In vivo the development of blood vessels from grafted EC spheroids and angiogenesis in tumors is impaired by CD44v6 blocking reagents, suggesting that the coreceptor function of CD44v6 for c-Met and VEGFR-2 is a promising target to block angiogenesis in pathologic conditions.

scholarly journals The Tyrosine Kinase Receptor RET Interacts in Vivo with Aryl Hydrocarbon Receptor-Interacting Protein to Alter Survivin Availability

2009 ◽  
Vol 30 (4) ◽  
pp. 413-413
Author(s):  
Manuela Vargiolu ◽  
Daniela Fusco ◽  
Ivana Kurelac ◽  
Dietmar Dirnberger ◽  
Ralf Baumeister ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Aryl Hydrocarbon Receptor ◽  
Tyrosine Kinase Receptor ◽  
Interacting Protein ◽  
Aryl Hydrocarbon
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