scholarly journals Src Tyrosine Kinase Inhibitor PP2 Markedly Enhances Ras-independent Activation of Raf-1 Protein Kinase by Phorbol Myristate Acetate and H2O2

2004 ◽  
Vol 279 (47) ◽  
pp. 48692-48701 ◽  
Author(s):  
Michael Lee ◽  
Ji-Young Kim ◽  
Wayne B. Anderson
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Phorbol Myristate Acetate ◽  
Kinase Inhibitor ◽  
Myristate Acetate ◽  
Src Tyrosine Kinase

Genistein augments prostaglandin-induced recovery of barrier function in ischemia-injured porcine ileum

2000 ◽  
Vol 278 (2) ◽  
pp. G207-G216 ◽  
Author(s):  
Anthony T. Blikslager ◽  
Malcolm C. Roberts ◽  
Karen M. Young ◽  
J. Marc Rhoads ◽  
Robert A. Argenzio
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Phorbol Myristate Acetate ◽  
Barrier Function ◽  
Kinase Inhibitor ◽  
Chloride Secretion ◽  
Myristate Acetate ◽  
Ussing Chambers ◽  
Kinase C

We have previously shown that PGE2 enhances recovery of transmucosal resistance ( R) in ischemia-injured porcine ileum via a mechanism involving chloride secretion. Because the tyrosine kinase inhibitor genistein amplifies cAMP-induced Cl− secretion, we postulated that genistein would augment PGE2-induced recovery of R. Porcine ileum subjected to 45 min of ischemia was mounted in Ussing chambers, and R and mucosal-to-serosal fluxes of [3H] N-formyl-methionyl-leucyl phenylalanine (FMLP) and [3H]mannitol were monitored as indicators of recovery of barrier function. Treatment with genistein (10− 4 M) and PGE2(10− 6 M) resulted in synergistic elevations in R and additive reductions in mucosal-to-serosal fluxes of [3H]FMLP and [3H]mannitol, whereas treatment with genistein alone had no effect. Treatment of injured tissues with genistein and either 8-bromo-cAMP (10− 4 M) or cGMP (10− 4 M) resulted in synergistic increases in R. However, treatment of tissues with genistein and the protein kinase C (PKC) agonist phorbol myristate acetate (10− 5–10− 6M) had no effect on R. Genistein augments recovery of Rin the presence of cAMP or cGMP but not in the presence of PKC agonists.

Secretin regulates paracellular permeability in canine gastric monolayers by a Src kinase-dependent pathway

2002 ◽  
Vol 283 (4) ◽  
pp. G893-G899 ◽  
Author(s):  
Monica C. Chen ◽  
Travis E. Solomon ◽  
Eduardo Perez Salazar ◽  
Robert Kui ◽  
Enrique Rozengurt ◽  
...  
Keyword(s):  
Gastric Mucosa ◽  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Paracellular Permeability ◽  
Maximal Response ◽  
Src Tyrosine Kinase

Previous studies found that epidermal growth factor (EGF) decreased paracellular permeability in gastric mucosa, but the other physiological regulators and the molecular mechanisms mediating these responses remain undefined. We investigated the role of secretin and Src in regulating paracellular permeability because secretin regulates gastric chief cell function and Src mediates events involving the cytoskeletal-membrane interface, respectively. Confluent monolayers were formed from canine gastric epithelial cells in short-term culture on Transwell filter inserts. Resistance was monitored in the presence of secretin with or without specific kinase inhibitors. Tyrosine phosphorylation of Src at Tyr416 was measured with a site-specific phosphotyrosine antibody. Basolateral, but not apical, secretin at concentrations from 1 to 100 nM dose dependently increased resistance; this response was rapid and sustained over hours. PP2 (10 μM), a selective Src tyrosine kinase inhibitor, but not the inactive isomer PP3, abolished the increase in resistance by secretin but only modestly attenuated apical EGF effects. AG-1478 (100 nM), a specific EGF receptor tyrosine kinase inhibitor, attenuated the resistance increase to EGF but not secretin. Secretin, but not EGF, induced tyrosine phosphorylation of Src at Tyr416 in a dose-dependent fashion, with the maximal response observed at 1 min. PP2, but not PP3, dramatically inhibited this tyrosine phosphorylation. Secretin increases paracellular resistance in gastric mucosa through a Src-mediated pathway, while the effect of EGF is Src independent. Src appears to mediate the physiological effects of this Gs-coupled receptor in primary epithelial cells.

The Tyrosine Kinase Inhibitor Adaphostin (NSC 680410), but Not Imatinib Mesylate, Inhibits Survival and Src Tyrosine Kinase Family- Triggered Signaling Pathways of MM Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3352-3352
Author(s):  
Klaus Podar ◽  
Melissa Simoncini ◽  
Yu-Tzu Tai ◽  
Martin Sattler ◽  
Kenji Ishitsuka ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Signaling Pathways ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
K562 Cells ◽  
Parp Cleavage ◽  
Src Tyrosine Kinase ◽  
Kinase Family ◽  
Long Term Treatment

Abstract The tyrosine kinase inhibitor adaphostin is a member of the tyrophostin family of small molecules that interfere with peptide binding rather, than targeting the kinase ATP-binding site. Adaphostin has therefore been examined as an alternative to the 2-phenylaminopyrimidine derivate imatinib mesylate, with remarkable efficacy in the treatment of chronic myeloic leukemia (CML). Previous studies show that adaphostin induces apoptosis: (1) in Bcr/Abl+ cells more rapidly than imatinib mesylate; (2) in imatinib mesylate resistant cells; and (3) in Bcr/ Abl - cells. Imatinib mesylate has minimal, if any activity in MM; the efficacy of adaphostin in multiple myeloma (MM) is unknown. Here we compare the effects of adaphostin and imatinib mesylate against human MM cells. Our results show concentration-dependent apoptosis in MM.1S, U266, OPM-2, INA-6, RPMI8226 and RPMI-Dox40 MM cells after treatment with adaphostin, but not with imatinib mesylate. Imatinib mesylate induced more than 50% apoptosis in K562 cells using concentrations as low as 1mM, which served as a positive control. Moreover, adaphostin, but not imatinib mesylate, induced caspase-9, caspase-8, and PARP cleavage, as well as downregulation of Mcl-1, in MM cells. Further results demonstrated that adaphostin induces peroxide production and DNA strand breaks after long-term treatment. Importantly MM cell proliferation induced by MM cell binding to BMSCs was abrogated by adaphostin- treatment. IL-6 and IGF-1 signaling and sequelae triggered by these cytokines are important growth, survival, and drug resistance factors in MM; conversely, adaphostin but not imatinib mesylate, inhibited phosphorylation of Src tyrosine kinase family, Akt-1, and ERK. Taken together, our studies in MM cells show that (1) adaphostin- inhibits IGF-1- and IL-6- triggered signaling pathways as well as (2) induces reactive oxygen species and apoptosis. These studies therefore provide the preclinical framework for its clinical evaluation to improve patient outcome in MM.

EFFECT OF SRC TYROSINE KINASE INHIBITOR, PP1, ON THE CYTOKINE RESPONSE INDUCED BY LIPOPOLYSACCHARIDE.

2005 ◽  
Vol 33 ◽  
pp. A139
Author(s):  
Sandra D Buttram ◽  
Patrick M Kochanek ◽  
Delbert G Gillespie ◽  
Zaichuan Mi ◽  
Edwin K Jackson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Cytokine Response ◽  
Src Tyrosine Kinase

scholarly journals Transforming growth factor-α increases tyrosine phosphorylation of microtubule-associated protein kinase in a small intestinal crypt cell line (IEC-6)

1994 ◽  
Vol 303 (2) ◽  
pp. 455-460 ◽  
Author(s):  
B L Oliver ◽  
R I Sha'afi ◽  
J J Hajjar
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Phosphorylation ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Intestinal Crypt ◽  
Small Intestinal ◽  
Intestinal Crypt Cell

The small intestinal crypt cell line (IEC-6) is an undifferentiated, untransformed, mitotically active cell used in this study to determine the effect of transforming growth factor-alpha (TGF-alpha) on tyrosine phosphorylation levels of cellular proteins. Thymidine incorporation increased maximally after addition of 2 ng/ml TGF-alpha for 24 h. At the same dose, TGF-alpha induced the tyrosine phosphorylation of proteins with approximate molecular masses of 42, 44, 52, 80, 150 and 175 kDa as shown by Western blots treated with anti-phosphotyrosine antibody. The most intense phosphorylation was seen in the 42 kDa (p42) and 44 kDa (p44) proteins, which were identified as two isoforms of microtubule-associated protein kinase (MAPK). This phosphorylation was seen as early as 5 min post stimulation and was dose dependent. Both p42 and p44 were found in the nucleus after stimulation, although a basal level of unphosphorylated protein was present before stimulation. The observed tyrosine phosphorylation of p42 and p44 was inhibited by genistein, a tyrosine kinase inhibitor, and tyrphostin 23, an epidermal growth factor receptor tyrosine kinase inhibitor. We conclude that MAPK is tyrosine phosphorylated in response to TGF-alpha stimulation of IEC-6 cells.

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