Effect of Dominant-Negative Epidermal Growth Factor Receptors on Cardiomyocyte Hypertrophy

Chan, Hsiu‐Wen; Jenkins, Anna; Pipolo, Luisa; Hannan, Ross D.; Thomas, Walter G.; Smith, Nicola J.

doi:10.1080/10799890600923187

Cited by 18 publications

(17 citation statements)

References 59 publications

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“…Although in a way expected, this observation provided important confidence and validation that the screen was sufficiently powerful to interrogate AT 1 R-EGFR transactivation. The finding that ErbB2 (the common dimerising partner for ErbB receptors) modulates the AT 1 R-EGFR transactivation response in our mammary epithelial cell model is consistent with previous studies suggesting that ErbB2 is required for AngII-mediated EGFR transactivation (Chan et al, 2006;Negro et al, 2006). It also corroborates data from other GPCRs, for example, the thrombin-dependent PAR1 activation in MDA-MB-231 breast cancer cells that transactivates EGFRErbB2 and increases cell invasiveness (Arora et al, 2008).…”

Section: Discussionsupporting

confidence: 80%

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

George

Purdue

Gould

et al. 2013

Journal of Cell Science

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SummaryThe angiotensin type 1 receptor (AT 1 R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT 1 R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT 1 R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT 1 R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT 1 R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer.

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Section: Discussionsupporting

confidence: 80%

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

George

Purdue

Gould

et al. 2013

Journal of Cell Science

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“…Subsequently, mouse models with ventricular specific deletion of ERBB2 or ERBB4 were found to recapitulate the cardiac phenotype observed in clinical trials (Crone et al, 2002;Ozcelik et al, 2002;Garcia-Rivello et al, 2005). More recently, signaling through EGFR was shown to provide cardioprotection against stress-induced injury, and reduction in EGFR activity impacts cardiomyocyte hypertrophy and survival (Pareja et al, 2003;Chan et al, 2006a;Chan et al, 2006b;Howes et al, 2006;Zhai et al, 2006). To date, no in vivo studies have specifically assessed the effects of chronically reduced EGFR activity on adult cardiac function, as might be expected with continuous drug exposure to TKIs, despite the fact that mutant mouse models have shown considerable similarities to drug-induced toxicities in the oncology clinic (Roberts et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Barrick

Chao

et al. 2008

Toxicology and Applied Pharmacology

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Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for three months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.

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“…ROS‐sensitive ERK kinases are influenced by ErbB4 signaling. It has been shown that HB‐EGF administration to ErbB4‐transfected HEK293 cells can induce ERK1/2 phosphorylation, and a similar phosphorylation amount was apparently obtained by neuregulin 1 (NRG1, a specific ErbB4 agonist) administration . NRG1 in vitro administration to PC12 cells or to adult cardiomyocytes stimulates ERK1/2 phosphorylation, which is inhibited in a dose‐dependent manner with AG1478.…”

Section: Discussionmentioning

confidence: 92%

“…We previously observed that SFR is inhibited by the protein tyrosin kinase inhibitor AG1478, at a concentration of 1 μmol/L, which is also capable of inhibiting the ErbB4, an alternative receptor for the HB‐EGF and the endogenous ligand involved in the process. Therefore, we explored the functional consequences of chronic EGFR silencing in the heart.…”

Section: Resultsmentioning

confidence: 99%

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Epidermal Growth Factor Receptor Silencing Blunts the Slow Force Response to Myocardial Stretch

Brea

Díaz

Escudero

et al. 2016

JAHA

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BackgroundMyocardial stretch increases force biphasically: the Frank‐Starling mechanism followed by the slow force response (SFR). Based on pharmacological strategies, we proposed that epidermal growth factor (EGF) receptor (EGFR or ErbB1) activation is crucial for SFR development. Pharmacological inhibitors could block ErbB4, a member of the ErbB family present in the adult heart. We aimed to specifically test the role of EGFR activation after stretch, with an interference RNA incorporated into a lentiviral vector (small hairpin RNA [shRNA]‐EGFR).Methods and ResultsSilencing capability of p‐shEGFR was assessed in EGFR‐GFP transiently transfected HEK293T cells. Four weeks after lentivirus injection into the left ventricular wall of Wistar rats, shRNA‐EGFR–injected hearts showed ≈60% reduction of EGFR protein expression compared with shRNA‐SCR–injected hearts. ErbB2 and ErbB4 expression did not change. The SFR to stretch evaluated in isolated papillary muscles was ≈130% of initial rapid phase in the shRNA‐SCR group, while it was blunted in shRNA‐EGFR–expressing muscles. Angiotensin II (Ang II)‐dependent Na+/H+ exchanger 1 activation was indirectly evaluated by intracellular pH measurements in bicarbonate‐free medium, demonstrating an increase in shRNA‐SCR–injected myocardium, an effect not observed in the silenced group. Ang II‐ or EGF‐triggered reactive oxygen species production was significantly reduced in shRNA‐EGFR–injected hearts compared with that in the shRNA‐SCR group. Chronic lentivirus treatment affected neither the myocardial basal redox state (thiobarbituric acid reactive substances) nor NADPH oxidase activity or expression. Finally, Ang II or EGF triggered a redox‐sensitive pathway, leading to p90RSK activation in shRNA‐SCR‐injected myocardium, an effect that was absent in the shRNA‐EGFR group.ConclusionsOur results provide evidence that specific EGFR activation after myocardial stretch is a key factor in promoting the redox‐sensitive kinase activation pathway, leading to SFR development.

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Effect of Dominant-Negative Epidermal Growth Factor Receptors on Cardiomyocyte Hypertrophy

Cited by 18 publications

References 59 publications

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Epidermal Growth Factor Receptor Silencing Blunts the Slow Force Response to Myocardial Stretch

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