4-Hydroxy-2-Nonenal Enhances Fibronectin Production by IMR-90 Human Lung Fibroblasts Partly via Activation of Epidermal Growth Factor Receptor-Linked Extracellular Signal-Regulated Kinase p44/42 Pathway

2002 ◽  
Vol 184 (3) ◽  
pp. 127-135 ◽  
Author(s):  
H Tsukagoshi
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Lung ◽  
Growth Factor Receptor ◽  
Lung Fibroblasts ◽  
Human Lung Fibroblasts ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Epidermal Growth

scholarly journals The UV (Ribotoxic) Stress Response of Human Keratinocytes Involves the Unexpected Uncoupling of the Ras-Extracellular Signal-Regulated Kinase Signaling Cascade from the Activated Epidermal Growth Factor Receptor

2002 ◽  
Vol 22 (15) ◽  
pp. 5380-5394 ◽  
Author(s):  
Mihail S. Iordanov ◽  
Remy J. Choi ◽  
Olga P. Ryabinina ◽  
Thanh-Hoai Dinh ◽  
Robert K. Bright ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Erk Signaling ◽  
Signaling Cascade ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Ribotoxic Stress Response ◽  
Epidermal Growth

ABSTRACT In mammals, UVB radiation is of biological relevance primarily for the cells of the epidermis. We report here the existence of a UVB response that is specific for proliferating human epidermal keratinocytes. Unlike other cell types that also display a UVB response, keratinocytes respond to UVB irradiation with a transient but potent downregulation of the Ras-extracellular signal-regulated kinase (ERK) signaling cascade. The downregulation of ERK precedes a profound decrease in the steady-state levels of cyclin D1, a mediator of the proliferative action of ERK. Keratinocytes exhibit high constitutive activity of the Ras-ERK signaling cascade even in culture medium lacking supplemental growth factors. The increased activity of Ras and phosphorylation of ERK in these cells are maintained by the autocrine production of secreted molecules that activate the epidermal growth factor receptor (EGFR). Irradiation of keratinocytes increases the phosphorylation of EGFR on tyrosine residues Y845, Y992, Y1045, Y1068, Y1086, Y1148, and Y1173 above the basal levels and leads to the increased recruitment of the adaptor proteins Grb2 and ShcA and of a p55 form of the regulatory subunit of the phosphatidylinositide 3-kinase to the UVB-activated EGFR. Paradoxically, however, UVB causes, at the same time, the inactivation of Ras and a subsequent dephosphorylation of ERK. By contrast, the signaling pathway leading from the activated EGFR to the phosphorylation of PKB/Akt1 is potentiated by UVB. The UVB response of keratinocytes appeared to be a manifestation of the more general ribotoxic stress response inasmuch as the transduction of the UVB-generated inhibitory signal to Ras and ERK required the presence of active ribosomes at the time of irradiation.

scholarly journals Signal Strength Dictates Phosphoinositide 3-Kinase Contribution to Ras/Extracellular Signal-Regulated Kinase 1 and 2 Activation via Differential Gab1/Shp2 Recruitment: Consequences for Resistance to Epidermal Growth Factor Receptor Inhibition

2007 ◽  
Vol 28 (2) ◽  
pp. 587-600 ◽  
Author(s):  
Carla Sampaio ◽  
Marie Dance ◽  
Alexandra Montagner ◽  
Thomas Edouard ◽  
Nicole Malet ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Signal Strength ◽  
Extracellular Signal Regulated Kinase ◽  
Egfr Activation ◽  
Extracellular Signal ◽  
Epidermal Growth ◽  
Phosphoinositide 3 Kinase

ABSTRACT Phosphoinositide 3-kinase (PI3K) participates in extracellular signal-regulated kinase 1 and 2 (ERK1-2) activation according to signal strength, through unknown mechanisms. We report herein that Gab1/Shp2 constitutes a PI3K-dependent checkpoint of ERK1-2 activation regulated according to signal intensity. Indeed, by up- and down-regulation of signal strength in different cell lines and through different methods, we observed that Gab1/Shp2 and Ras/ERK1-2 in concert become independent of PI3K upon strong epidermal growth factor receptor (EGFR) stimulation and dependent on PI3K upon limited EGFR activation. Using Gab1 mutants, we observed that this conditional role of PI3K is dictated by the EGFR capability of recruiting Gab1 through Grb2 or through the PI3K lipid product PIP3, according to a high or weak level of receptor stimulation, respectively. In agreement, Grb2 siRNA generates, in cells with maximal EGFR stimulation, a strong dependence on PI3K for both Gab1/Shp2 and ERK1-2 activation. Therefore, Ras/ERK1-2 depends on PI3K only when PIP3 is required to recruit Gab1/Shp2, which occurs only under weak EGFR mobilization. Finally, we show that, in glioblastoma cells displaying residual EGFR activation, this compensatory mechanism becomes necessary to efficiently activate ERK1-2, which could probably contribute to tumor resistance to EGFR inhibitors.

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