scholarly journals Endosomal Signaling of Epidermal Growth Factor Receptor Stimulates Signal Transduction Pathways Leading to Cell Survival

2002 ◽  
Vol 22 (20) ◽  
pp. 7279-7290 ◽  
Author(s):  
Yi Wang ◽  
Steven Pennock ◽  
Xinmei Chen ◽  
Zhixiang Wang
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Kinase Inhibitor ◽  
Nucleation Site ◽  
Signal Transduction Pathways ◽  
Egfr Signaling ◽  
Endosomal Signaling ◽  
Epidermal Growth

ABSTRACT In spite of intensified efforts to understand cell signaling from endosomes, there is no direct evidence demonstrating that endosomal signaling is sufficient to activate signal transduction pathways and no evidence to demonstrate that endosomal signaling is able to produce a biological outcome. The lack of breakthrough is due in part to the lack of means to generate endosomal signals without plasma membrane signaling. In this paper, we report the establishment of a system to specifically activate epidermal growth factor (EGF) receptor (EGFR) when it endocytoses into endosomes. We treated cells with EGF in the presence of AG-1478, a specific EGFR tyrosine kinase inhibitor, and monensin, which blocks the recycling of EGFR. This treatment led to the internalization of nonactivated EGF-EGFR complexes into endosomes. The endosome-associated EGFR was then activated by removing AG-1478 and monensin. During this procedure we did not observe any surface EGFR phosphorylation. We also achieved specific activation of endosome-associated EGFR without using monensin. By using this system, we provided original evidence demonstrating that (i) the endosome can serve as a nucleation site for the formation of signaling complexes, (ii) endosomal EGFR signaling is sufficient to activate the major signaling pathways leading to cell proliferation and survival, and (iii) endosomal EGFR signaling is sufficient to suppress apoptosis induced by serum withdrawal.

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

Evidence for epidermal growth factor (EGF)-induced intermolecular autophosphorylation of the EGF receptors in living cells

1990 ◽  
Vol 10 (8) ◽  
pp. 4035-4044
Author(s):  
A M Honegger ◽  
A Schmidt ◽  
A Ullrich ◽  
J Schlessinger
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Egf Receptor ◽  
Living Cells ◽  
Egf Receptors ◽  
Receptor Molecule ◽  
Epidermal Growth ◽  
Negative Mutant

In response to epidermal growth factor (EGF) stimulation, the intrinsic protein tyrosine kinase of EGF receptor is activated, leading to tyrosine phosphorylation of several cellular substrate proteins, including the EGF receptor molecule itself. To test the mechanism of EGF receptor autophosphorylation in living cells, we established transfected cell lines coexpressing a kinase-negative point mutant of EGF receptor (K721A) with an active EGF receptor mutant lacking 63 amino acids from its carboxy terminus. The addition of EGF to these cells caused tyrosine phosphorylation of the kinase-negative mutant by the active receptor molecule, demonstrating EGF receptor cross-phosphorylation in living cells. After internalization the kinase-negative mutant and CD63 have separate trafficking pathways. This limits their association and the extent of cross-phosphorylation of K721A by CD63. The coexpression of the kinase-negative mutant together with active EGF receptors in the same cells suppressed the mitogenic response toward EGF as compared with that in cells that express active receptors alone. The presence of the kinase-negative mutant functions as a negative dominant mutation suppressing the response of active EGF receptors, probably by interfering with EGF-induced signal transduction. It appears, therefore, that crucial events of signal transduction occur before K721A and active EGF receptors are separated by their different endocytic itineraries.

scholarly journals Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein

1998 ◽  
Vol 334 (1) ◽  
pp. 189-195 ◽  
Author(s):  
Hong-Hee KIM ◽  
Ulka VIJAPURKAR ◽  
Nathan J. HELLYER ◽  
Dolores BRAVO ◽  
John G. KOLAND
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Egf Receptor ◽  
Tyrosine Kinase Activity ◽  
Epidermal Growth ◽  
Protein Tyrosine Kinase Activity

The role of protein tyrosine kinase activity in ErbB3-mediated signal transduction was investigated. ErbB3 was phosphorylated in vivo in response to either heregulin (HRG) in cells expressing both ErbB3 and ErbB2, or epidermal growth factor (EGF) in cells expressing both ErbB3 and EGF receptor. A recombinant receptor protein (ErbB3-K/M, in which K/M stands for Lys → Met amino acid substitution) containing an inactivating mutation in the putative ATP-binding site was also phosphorylated in response to HRG and EGF. Both the wild-type ErbB3 and mutant ErbB3-K/M proteins transduced signals to phosphatidylinositol 3-kinase, Shc and mitogen-activated protein kinases. Separate kinase-inactivating mutations in the EGF receptor and ErbB2 proteins abolished ErbB3 phosphorylation and signal transduction activated by EGF and HRG respectively. Hence the protein tyrosine kinase activity necessary for growth factor signalling via the ErbB3 protein seems to be provided by coexpressed EGF and ErbB2 receptor proteins.

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Trial of ZD1839, a Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Five Selected Solid Tumor Types

2002 ◽  
Vol 20 (21) ◽  
pp. 4292-4302 ◽  
Author(s):  
J. Baselga ◽  
D. Rischin ◽  
M. Ranson ◽  
H. Calvert ◽  
E. Raymond ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Egfr Signaling ◽  
Epidermal Growth ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

Activated epidermal growth factor receptor (ErbB1) protects the heart against stress-induced injury in mice

2003 ◽  
Vol 285 (2) ◽  
pp. R455-R462 ◽  
Author(s):  
Miguel Pareja ◽  
Olga Sánchez ◽  
Jordi Lorita ◽  
Maria Soley ◽  
Ignasi Ramírez
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mononuclear Cells ◽  
Egf Receptor ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Epidermal Growth ◽  
Heart Injury ◽  
Exogenous Ligands

Acute, high-intensity stress induces necrotic lesions in the heart. We found that restraint-and-cold (4°C) exposure (RCE) raises plasma lactate dehydrogenase (LDH), creatine kinase (CK), and transaminase activity in a time-dependent manner, with a peak value 7 h after stimulus cessation. At 24 h, signs of necrotic lesions were observed in paraffin sections stained with hematoxylineosin: focal accumulation of mononuclear cells in subendocardial areas of the left ventricle wall and focal hemorrhage in papillary muscles. In contrast, intermale fighting (IF) did not increase plasma CK activity, although LDH and transaminase activities did increase. In IF, no histological evidence of heart injury was observed. Because IF, but not RCE, increased plasma epidermal growth factor (EGF) concentration by ∼1,000-fold, we hypothesized that EGF receptor (ErbB1) activation may protect the heart against stress-induced injury. To examine this hypothesis, we injected the ErbB1 tyrosine kinase inhibitor tyrphostin AG-1478 (25 mg/kg ip) immediately before mice were exposed to IF. After 3 h, plasma activities of LDH-1 and CK increased. Plasma enzyme activities were as low in control mice (injected with vehicle alone) as in nonfighting mice. In the last experiment, we injected EGF (0.25 mg/kg ip) 20 min before exposing mice to RCE. After 7 h, plasma LDH-1 and CK activities were significantly lower in these animals than in mice injected with vehicle. The effect required ErbB1 activation, because simultaneous administration of AG-1478 completely abolished the effect of exogenous EGF. We conclude that activated ErbB1, by endogenous or exogenous ligands, may protect the heart against stress-induced injury.

Alternative Pathways of Epidermal Growth Factor Receptor Mediated Contractile Force in NR6 Fibroblasts

1999 ◽  
Author(s):  
Fred D. Allen ◽  
Clara F. Asnes ◽  
Alan Wells ◽  
Elliot L. Elson ◽  
Douglas A. Lauffenburger
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Mapk Pathway ◽  
Contractile Force ◽  
Mitogen Activated Protein Kinase ◽  
Egfr Signaling ◽  
Signaling Mechanism ◽  
Force Increase ◽  
Epidermal Growth

Abstract We investigated the contractile force response to epidermal growth factor (EGF) stimulation in 3T3-derived NR6 fibroblast cells in order to determine significant pathways of biochemical signaling that mediate the response. We examined the force generating specificity of the EGF receptor (EGFR) signaling mechanism by using mutant NR6 fibroblasts expressing variations of the EGFR construct. The wild-type (WT) cell presented the complete internalizing EGFR signaling construct while the c’973 cell presented an internalization-defective EGFR construct, and the M721 cell presented a kinase-defective EGFR construct making it signaling inert. Additionally we examined the roles of the phospholipasc C-γ (PLCγ) pathway by using the PLC inhibitor U73122 (1 μM) and the mitogen activated protein kinase (MAPK) pathway using the inhibitor PD98059 (10 μM) in the observed contractile force responses. We found that the WT cells showed a rapid but transient force increase within the first hour post-stimulation and the c’973 showed a more gradual increase in force which it sustained for several hours post-stimulation. Blocking the PLCγ activation in the WT cells reduced the peak force increase by 50% while blocking MAPK did not affect the force development in either WT or c’973 cells.

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