Cross talk between epidermal growth factor (EGF) receptor and extra nuclear steroid receptors in cell lines

Migliaccio, Antimo; Castoria, Gabriella; Giovannelli, Pia; Auricchio, Ferdinando

doi:10.1016/j.mce.2010.06.014

Cited by 23 publications

(17 citation statements)

References 40 publications

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“…DHTbound androgen receptor binds to the SRC SH3 domain, thereby releasing the kinase domain. SRC can then modulate ERK1/2 by phosphorylating SHC1 proteins to initiate the Ras-Raf-MEK-ERK pathway (24) or by phosphorylating EGFRs and increasing their ligand-induced activity (25). The experiments described herein suggest that DHT potentiates ERK1/2 signaling within 1 hour, leading us to hypothesize that androgens regulate ERK activation by a nontranscriptional mechanism.…”

mentioning

confidence: 70%

Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

Lee

Smith

Murray

et al. 2014

Am J Respir Cell Mol Biol

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Lung maturation is regulated by interactions between mesenchymal and epithelial cells, and is delayed by androgens. FibroblastType II cell communications are dependent on extracellular signalregulated kinases (ERK) 1/2 activation by the ErbB receptor ligands epidermal growth factor (EGF), transforming growth factor (TGF)-a, and neuregulin (Nrg). In other tissues, dihydrotestosterone (DHT) has been shown to activate SRC by a novel nontranscriptional mechanism, which phosphorylates EGF receptors to potentiate EGF-induced ERK1/2 activation. This study sought to determine if DHT potentiates EGFR signaling by a nontranscriptional mechanism. Embryonic day (E)17 fetal lung cells were isolated from dams treated with or without DHT since E12. Cells were exposed to 30 ng/ml DHT for periods of 30 minutes to 3 days before being stimulated with 100 ng/ml EGF, TGF-a, or Nrg for up to 30 minutes. Lysates were immunoblotted for ErbB and SRC pathway signaling intermediates. DHT increased ERK1/2 activation by EGF, TGF-a, and Nrg in fibroblasts and Type II cells. Characterization in fibroblasts showed that potentiation of the EGF pathway was significant after 60 minutes of DHT exposure and persisted in the presence of the translational inhibitor cycloheximide. SRC and EGF receptor phosphorylation was increased by DHT, as was EGF-induced SHC1 phosphorylation and subsequent association with GRB2. Finally, SRC silencing, SRC inhibition with PP2, and overexpression of a dominantnegative SRC each prevented DHT from increasing EGF-induced ERK1/2 phosphorylation. These results suggest that DHT activates SRC to potentiate the signaling pathway leading from the EGF receptor to ERK activation in primary fetal lung fibroblasts.

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mentioning

confidence: 70%

Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

Lee

Smith

Murray

et al. 2014

Am J Respir Cell Mol Biol

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“…Another model of this cross-talk has been proposed in which the ligand-activated EGFR phosphorylates ESR1 on tyrosine 537, thereby inducing ESR1-SRC association and kinase activation. SRC phosphorylates EGFR, which amplifies receptor activity and induces signal transduction activation (reviewed by Migliaccio et al 2010). PPT-induced ERK1/2 phosphorylation in the corpus of the epididymis was decreased by the EGFR kinase inhibitor, which indicates the involvement of ESR1-SRC-EGFR in the activation of ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor ESR1 mediates activation of ERK1/2, CREB, and ELK1 in the corpus of the epididymis

Cavalcanti

Lucas

Lazari

et al. 2015

Journal of Molecular Endocrinology

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Expression of the estrogen receptor ESR1 is higher in the corpus than it is in the initial segment/caput and cauda of the epididymis. ESR1 immunostaining in the corpus has been localized not only in the nuclei but also in the cytoplasm and apical membrane, which indicates that ESR1 plays a role in membrane-initiated signaling. The present study investigated whether ESR1 mediates the activation of rapid signaling pathways by estradiol (E 2 ) in the epididymis. We investigated the effect of E 2 and the ESR1-selective agonist (4,4 0 ,4 0 0 -(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) on the activation of extracellular signal-regulated protein kinases (ERK1/2), CREB protein, and ETS oncogene-related protein (ELK1). Treatment with PPT did not affect ERK1/2 phosphorylation in the cauda, but it rapidly increased ERK1/2 phosphorylation in the initial segment/caput and corpus of the epididymis. PPT also activated CREB and ELK1 in the corpus of the epididymis. The PPT-induced phosphorylation of ERK1/2, CREB, and ELK1 was blocked by the ESR1-selective antagonist MPP and by pretreatment with a non-receptor tyrosine kinase SRC inhibitor, an EGFR kinase inhibitor, an MEK1/2 inhibitor, and a phosphatidylinositol-3-kinase inhibitor. In conclusion, these results indicate that the corpus, which is a region with high expression of the estrogen receptor ESR1, is a major target in the epididymis for the activation of rapid signaling by E 2 . The sequence of events that follow E 2 interaction with ESR1 includes the SRC-mediated transactivation of EGFR and the phosphorylation of ERK1/2, CREB, and ELK1. This rapid estrogen signaling may modulate gene expression in the corpus of the epididymis, and it may play a role in the dynamic microenvironment of the epididymal lumen.

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“…In hormone-responsive cells expressing both AR and ER (α and/or β), such as prostate and breast cancers, AR/ER/Src association plays a crucial role in activation of Src signals triggered by EGF and/or sex hormones (25,28). It was noteworthy that either AR or ER antagonist sufficiently inhibited this EGF-mediated association and subsequent stimulatory effects (28).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies in prostate and breast cancers demonstrated that EGF induced AR/ER/Src association, resulting in activation of Src signaling (25,28) and that Src signals phosphorylated tyrosine residue of AR, provoking its transactivation and cell proliferation (29). We therefore investigated whether EGF induced AR/ER/ Src complex formation in UMUC3 which is ERα-negative/ ERβ-positive (figure not shown).…”

Section: Egf Induces Ar Association With Er and Srcmentioning

confidence: 97%

“…Specifically, in prostate cancer cells, AR signals upregulate EGFR and ERBB2 gene expression, whereas activation of EGFR and ERBB2 modulates AR functions (20)(21)(22)(23)(24). It has also been shown that the assembly of the EGFR/AR/ER/ Src signaling complex is crucial for proliferation of prostate and breast cancer cells triggered by androgens, estrogens and/ or EGF (25). In contrast, the relationship between the AR and EGFR pathways in bladder cancer remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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1063 Epidermal Growth Factor Induces Bladder Cancer Cell Proliferation Through Activation of Androgen Receptor

Izumi¹,

Zheng²,

Zaengle³

et al. 2012

Journal of Urology

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Abstract. Androgen receptor (AR) signals have been suggested to contribute to bladder tumorigenesis and cancer progression. Activation of epidermal growth factor receptor (EGFR) also leads to stimulation of bladder tumor growth. However, crosstalk between AR and EGFR pathways in bladder cancer remains uncharacterized. We have recently shown that androgens activate the EGFR pathway in bladder cancer cells. The purpose of this study was to investigate the effects of EGF on AR activity in bladder cancer. EGF increased AR transcriptional activity by 1.2-, 1.9-and 2.0-fold in UMUC3, 5637-AR and J82-AR cell lines, respectively, over mock treatment and a specific EGFR inhibitor, PD168393, antagonized the EGF effect. Combined treatment of EGF and dihydrotestosterone (DHT) further induced AR transactivation while an AR antagonist, hydroxyflutamide (HF), abolished the effect of not only DHT but also EGF. In growth assays, EGF alone/DHT alone/EGF+DHT increased cell numbers by 16/12/19%, 6/14/18% and 30/12/38% in UMUC3-control-shRNA, 5637-AR and J82-AR, respectively, whereas the effects of EGF were marginal or less significant in UMUC3-AR-shRNA (8%) or AR-negative 5637-V (<1%) and J82-V (17%) cells. HF treatment at least partially counteracted the EGF effect on the growth of AR-positive cells. Western blotting demonstrated that EGF, especially in the presence of DHT, upregulated the expression of the p160 coactivator TIF2 and HF again blocked this stimulation. Co-immunoprecipitation revealed the association between AR and estrogen receptor (ER)-β or Src in UMUC3 cells and stronger associations with EGF treatment, implying the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and cell growth. Current results, thus, suggest that EGF promotes bladder cancer cell proliferation via modulation of AR signals. Taken together with our previous findings, crosstalk between EGFR and AR pathways can play an important role in the progression of bladder cancer.

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Cross talk between epidermal growth factor (EGF) receptor and extra nuclear steroid receptors in cell lines

Cited by 23 publications

References 40 publications

Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

Estrogen receptor ESR1 mediates activation of ERK1/2, CREB, and ELK1 in the corpus of the epididymis

1063 Epidermal Growth Factor Induces Bladder Cancer Cell Proliferation Through Activation of Androgen Receptor

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