scholarly journals Fast receptor-induced formation of glycerophosphoinositol-4-phosphate, a putative novel intracellular messenger in the Ras pathway.

1997 ◽  
Vol 8 (3) ◽  
pp. 443-453 ◽  
Author(s):  
M Falasca ◽  
A Carvelli ◽  
C Iurisci ◽  
R G Qiu ◽  
M H Symons ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cyclic Amp ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Ras Pathway ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase ◽  
Intracellular Messenger ◽  
In Cells

Glycerophosphoinositols are phosphoinositide metabolites whose levels are constitutively elevated in Ras-transformed cells. Here, we show that one of these compounds, glycerophosphoinositol-4-phosphate (GroPIns-4-P) responds acutely to the stimulation of the epidermal growth factor receptor, with a fast, massive and transient increase. The mechanism leading to GroPIns-4-P formation involves the activation of phosphoinositide-3 kinase and the small GTP-binding protein Rac, since GroPIns-4-P was neither formed in cells expressing the dominant negative form of Rac nor in cells treated with the phosphoinositide-3 kinase inhibitor wortmannin. GroPIns-4-P has been previously shown to inhibit adenylyl cyclase. Accordingly, epidermal growth factor also decreased the basal, cholera toxin-stimulated, and forskolin-stimulated cyclic AMP levels with kinetics similar to those of GroPIns-4-P formation, suggesting that GroPIns-4-P mediates this inhibitory effect. The hormone-induced formation of GroPIns-4-P was detected in several cell lines of various origin, suggesting that GroPIns-4-P is a novel intracellular messenger of the Ras pathway, possibly able to convey information from tyrosine kinase receptors to the cyclic AMP cascade.

scholarly journals A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization.

1991 ◽  
Vol 11 (3) ◽  
pp. 1454-1463 ◽  
Author(s):  
O Kashles ◽  
Y Yarden ◽  
R Fischer ◽  
A Ullrich ◽  
J Schlessinger
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Living Cells ◽  
Dominant Negative ◽  
Egf Receptors ◽  
Wild Type ◽  
Dominant Negative Mutation ◽  
Epidermal Growth ◽  
Mutant Receptors ◽  
In Cells

Recent studies provide evidence that defective receptors can function as a dominant negative mutation suppressing the action of wild-type receptors. This causes various diminished responses in cell culture and developmental disorders in murine embryogenesis. Here, we describe a model system and a potential mechanism underlying the dominant suppressing response caused by defective epidermal growth factor (EGF) receptors. We used cultured 3T3 cells coexpressing human wild-type receptors and an inactive deletion mutant lacking most of the cytoplasmic domain. When expressed alone, EGF was able to stimulate the dimerization of either wild-type or mutant receptors in living cells as revealed by chemical covalent cross-linking experiments. In response to EGF, heterodimers and homodimers of wild-type and mutant receptors were observed in cells coexpressing both receptor species. However, only homodimers of wild-type EGF receptors underwent EGF-induced tyrosine autophosphorylation in living cells. These results indicate that the integrity of both receptor moieties within receptor dimers is essential for kinase activation and autophosphorylation. Moreover, the presence of mutant receptors in cells expressing wild-type receptors diminished the number of high-affinity binding sites for EGF, reduced the rate of receptor endocytosis and degradation, and diminished biological signalling via EGF receptors. We propose that heterodimerization with defective EGF receptors functions as a dominant negative mutation suppressing the activation and response of normal receptors by formation of unproductive heterodimers.

A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization

1991 ◽  
Vol 11 (3) ◽  
pp. 1454-1463
Author(s):  
O Kashles ◽  
Y Yarden ◽  
R Fischer ◽  
A Ullrich ◽  
J Schlessinger
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Living Cells ◽  
Dominant Negative ◽  
Egf Receptors ◽  
Wild Type ◽  
Dominant Negative Mutation ◽  
Epidermal Growth ◽  
Mutant Receptors ◽  
In Cells

Recent studies provide evidence that defective receptors can function as a dominant negative mutation suppressing the action of wild-type receptors. This causes various diminished responses in cell culture and developmental disorders in murine embryogenesis. Here, we describe a model system and a potential mechanism underlying the dominant suppressing response caused by defective epidermal growth factor (EGF) receptors. We used cultured 3T3 cells coexpressing human wild-type receptors and an inactive deletion mutant lacking most of the cytoplasmic domain. When expressed alone, EGF was able to stimulate the dimerization of either wild-type or mutant receptors in living cells as revealed by chemical covalent cross-linking experiments. In response to EGF, heterodimers and homodimers of wild-type and mutant receptors were observed in cells coexpressing both receptor species. However, only homodimers of wild-type EGF receptors underwent EGF-induced tyrosine autophosphorylation in living cells. These results indicate that the integrity of both receptor moieties within receptor dimers is essential for kinase activation and autophosphorylation. Moreover, the presence of mutant receptors in cells expressing wild-type receptors diminished the number of high-affinity binding sites for EGF, reduced the rate of receptor endocytosis and degradation, and diminished biological signalling via EGF receptors. We propose that heterodimerization with defective EGF receptors functions as a dominant negative mutation suppressing the activation and response of normal receptors by formation of unproductive heterodimers.

scholarly journals Phosphatidylinositol 3-Kinase Activity Is Required for Epidermal Growth Factor to Suppress Proteolysis

2002 ◽  
Vol 13 (4) ◽  
pp. 903-909
Author(s):  
Harold A. Franch ◽  
Xiaonan Wang ◽  
Sira Sooparb ◽  
Nikia S. Brown ◽  
Jie Du
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Protein Breakdown ◽  
Phosphatidylinositol 3 Kinase ◽  
Class 1 ◽  
Epidermal Growth ◽  
Phosphatidylinositol 3

ABSTRACT. Suppression of protein breakdown occurs commonly in cell growth, but the pathways responsible for controlling proteolysis are poorly understood. Protein breakdown in NRK-52E renal epithelial cells treated with epidermal growth factor (EGF) and intracellular signaling inhibitors or dominant negative signaling molecules contained in an adenoviral vector were measured. The tyrosine kinase inhibitor, herbimycin A, eliminated the suppression of proteolysis induced by EGF. In contrast, the Src inhibitor, PP1, had no effect. Expression of dominant negative H-RasY57 blocked the ability of EGF to stimulate downstream targets of Ras and also reduced the ability of EGF to suppress proteolysis. Inhibiting MEK did not influence the ability of EGF to suppress proteolysis, but the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY249002, stimulated basal proteolysis and completely eliminated the proteolytic response to EGF. Use of an adenovirus that expresses a dominant negative p85 subunit of class 1 PI 3-kinase completely blocked the ability of EGF to suppress proteolysis, whereas use of an adenovirus expressing a K227E constitutively active p110 subunit reproduced the reduction in protein breakdown. It was concluded that EGF suppresses proteolysis by a mechanism that involves Ras and class 1 PI 3-kinase.

947: Chemopreventive Effects of COX-2 Inhibitor and Epidermal Growth Factor (EGF)-Receptor Kinase Inhibitor on Rat Urinary Bladder Tumorigenesis

2004 ◽  
Vol 171 (4S) ◽  
pp. 251-251
Author(s):  
Kazunori Hattori ◽  
Katsuyuki Iida ◽  
Akira Johraku ◽  
Sadamu Tsukamoto ◽  
Taeko Asano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Urinary Bladder ◽  
Egf Receptor ◽  
Kinase Inhibitor ◽  
Receptor Kinase ◽  
Rat Urinary Bladder ◽  
Epidermal Growth ◽  
Cox 2
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