Signal characteristics of G protein-transactivated EGF receptor

Daub, Henrik; Wallasch, Christian; Lankenau, Andreas; Herrlich, Andreas; Ullrich, Axel

doi:10.1093/emboj/16.23.7032

Cited by 615 publications

(532 citation statements)

References 68 publications

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“…In the present study, we Stimulation of EGF receptor is known to induce cell proliferation [2,20]. This is associated with ERK activation at 5-60 min following the stimulation of EGF receptor [21,22], that is occasionally accompanied by JNK activation [23][24][25]. In SVHK cells, EGF activated ERK and JNK, that were associated with cell proliferation.…”

Section: Discussionmentioning

confidence: 89%

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

Takahashi

Kinouchi

Manabe

et al. 2001

Journal of Dermatological Science

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ELSEVIER, Nakamura, S; Takahashi, H; Kinouchi, M; Manabe, A; Ishida-Yamamoto, A; Hashimoto, Y; Iizuka, H, JOURNAL OF DERMATOLOGICAL SCIENCE, 25(2), 139-149, 2001. authorSV-40 transformed human keratinocytes (SVHK cells) were stimulated with epidermal growth factor (EGF)2 and ultraviolet B (UVB) irradiation. Following the stimulation, cell growth, apoptosis, and the activities of mitogen-activated protein (MAP) kinase families were analyzed. EGF (100ng/ml) increased SVHK cell number compared with control cells cultured in serum-free DMEM medium. The EGF-stimulated cells did not show DNA fragmentation. In contrast, UVB irradiation (40mJ/cm2) markedly decreased viable cell number, that was accompanied with DNA fragmentation. EGF stimulated extracellular signal-regulated kinase (ERK) and stress-activated protein kinase/c-Jun N-terminal kinase (JNK). Following the EGF stimulation, phosphorylated ERK and JNK were detected by phospho-p42/44 MAP kinase antibody and phospho-SAPK/JNK antibody, respectively. On the other hand, UVB irradiation stimulated the phosphorylation of p38 and JNK but not of ERK. The stimulation of ERK and JNK induced by EGF was observed earlier than the stimulation of p38 and JNK induced by UVB. PD98059, a specific MAP kinase kinase (MAPKK) 1 (also referred to as MEK1) inhibitor, inhibited EGF-dependent cell proliferation, that was associated with the inhibition of ERK and JNK phosphorylation. In contrast, UVB-induced overall cell death was not significantly affected by PD98059, that inhibited phosphorylation of JNK but not of p38. PD98059, however, significantly augmented UVB-induced cell death earlier time points (30min - 2 h). These results indicate that ERK and JNK are activated following EGF stimulation, that might be associated with cell proliferation. On the other hand, UVB-induced apoptosis seems to be mostly associated with the activation of p38. JNK stimulation might provide an anti-apoptotic tonus during the UVB-induced, p38-associated SVHK cell death

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Section: Discussionmentioning

confidence: 89%

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

Takahashi

Kinouchi

Manabe

et al. 2001

Journal of Dermatological Science

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“…Whole cell lysates from FHL-124 cells were prepared using Daub lysis buffer (Daub et al, 1997) supplemented with 1 mM phenylmethylsulfonyl fluoride (PMSF) and 10 mg/ml aprotinin for 20 min on ice and centrifuged at 13 000 rpm for 10 min. The protein concentration in the supernatant was determined using the bicinchoninic acid protein assay (Pierce, Rockford, IL).…”

Section: Western Blot Analysismentioning

confidence: 99%

Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells

Radreau

Rhodes

Mithen

et al. 2009

Experimental Eye Research

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Keywords: quercetin flavonoid antioxidant diet lens HIF-1a hypoxia VEGF a b s t r a c t Quercetin is a dietary bioflavonoid which has been shown to inhibit lens opacification in a number of models of cataract. The objectives of this study were to determine gene expression changes in human lens epithelial cells in response to quercetin and to investigate in detail the mechanisms underlying the responses. FHL-124 cells were treated with quercetin (10 mM) and changes in gene expression were measured by microarray. It was found that 65% of the genes with increased expression were regulated by the hypoxia-inducible factor-1 (HIF-1) pathway. Quercetin (10 and 30 mM) induced a time-dependent increase in HIF-1a protein levels. Quercetin (30 mM) was also responsible for a rapid and long-lasting translocation of HIF-1a from the cytoplasm to the nucleus. Activation of HIF-1 signaling by quercetin was confirmed by qRT-PCR which showed upregulation of the HIF-1 regulated genes EPO, VEGF, PGK1 and BNIP3. Analysis of medium taken from FHL-124 cells showed a sustained dose-dependent increase in VEGF secretion following quercetin treatment. The quercetin-induced increase and nuclear translocation of HIF-1a was reversed by addition of excess iron (100 mM). These results demonstrate that quercetin activates the HIF-1 signaling pathway in human lens epithelial cells.

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“…Using NT as a prototype neuropeptide, and knowing that the NT receptor is a GPCR (Seethalakshmi et al, 1997), we hypothesized that NT secreted by NE-like cells can act upon prostate cancer cells to transactivate the EGFR as described in the Introduction (Daub et al, 1996(Daub et al, , 1997Prenzel et al, 1999). To test this hypothesis, PC3 cells were pre-incubated with SR48692, a potent and selective non-peptide antagonist for the neurotensin receptor (NTR) (Gully et al, 1993) with specificity for NTR1 (Labbe-Jullie et al, 1998).…”

Section: Nt-induced Transactivation Of the Egfrmentioning

confidence: 99%

“…Numerous, recent reports have shown that transactivation of the epidermal growth factor (EGF) receptor (EGFR) is critical for the mitogenic activity of multiple GPCR agonists (Daub et al, 1996(Daub et al, , 1997Prenzel et al, 1999;Madarame et al, 2003;Xiao et al, 2003;Zhao et al, 2004) and that EGFR transactivation requires metalloproteinase (MMP) cleavage of pro-heparin-binding EGF-like growth factor (pro-HB-EGF) into HB-EGF, which is released from the cell surface to bind the EGFR in an autocrine or paracrine manner (Prenzel et al, 1999;Madarame et al, 2003;Santiskulvong and Rozengurt, 2003;Yano et al, 2004;Zhao et al, 2004;Hassan and Carraway, 2006). However, the detailed signaling events following EGFR transactivation that are required for mitogenic activation are not fully understood, particularly in prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway

2006

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Neuroendocrine (NE)-like cells are hypothesized to contribute to the progression of prostate cancer by producing factors that enhance the growth, survival or metastatic capabilities of surrounding tumor cells. Many of the factors known to be secreted by NE-like cells, such as neurotensin (NT), parathyroid hormone-related peptide, serotonin, bombesin, etc., are agonists for G-proteincoupled receptors, but the signaling pathways activated by these agonists in prostate tumor cells are not fully defined. Identification of such pathways could provide insights into novel methods of treating late-stage disease. Using conditioned culture medium (CM) from LNCaPderived NE-like cells (as a source of these agonists) or NT (a prototypical component of CM) to treat PC3 cells, we found that the epidermal growth factor (EGF) receptor (EGFR) was transactivated and that such activation was required for maximal PC3 cell mitogenesis, as measured by 5-bromo-2 0 -deoxy-uridine incorporation or cell number. NT also induced a time-dependent increase in EGFR Tyr 845 phosphorylation and phosphorylation of c-Src and signal transducer and activator of transcription 5b (Stat5b) (a downstream effector of Tyr 845 ), events that were blocked by specific inhibition of c-Src (which mediates Tyr 845 phosphorylation of EGFR) or of EGFR. Introduction of mutant forms of EGFR (Tyr 845 ) or Stat5b in PC3 cells, or treatment with selective, catalytic inhibitors of EGFR, c-Src and matrix metalloproteinases (MMPs) resulted in the loss of NT-induced stimulation of DNA synthesis, relative to wild-type controls. These data indicate that the mitogenic effect of NT on prostate cancer cells requires transactivation of the EGFR by MMPs and a novel downstream pathway involving c-Src, phosphorylation of EGFR Tyr 845 and activation of Stat5b.

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Signal characteristics of G protein-transactivated EGF receptor

Cited by 615 publications

References 68 publications

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

Differential phosphorylation of mitogen-activated protein kinase families by epidermal growth factor and ultraviolet B irradiation in SV40-transformed human keratinocytes

Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells

Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway

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