Tackling the EGFR in pathological tissue remodelling

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

doi:10.1016/j.pupt.2005.04.005

Cited by 27 publications

(20 citation statements)

References 35 publications

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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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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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“…It has been postulated that MMPs may cleave membrane-bound precursor proteins and release EGF-like ligands that subsequently bind to EGFR (Chan et al, 2006). Angiotensin II-induced cardiomyocyte hypertrophy has been associated with EGFR-transactivated p44/42 signaling (Thomas et al, 2002 fra-1 induction in cigarette-smoke-treated lung epithelial cells (Zhang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…These signals are initiated by receptor binding of EGF and EGF-like ligands, which are expressed as transmembrane precursor proteins and need to be cleaved by proteases to release the mature form (Chan et al, 2006). It has been reported that angiotensin II can mediate cardiomyocyte hypertrophic growth pathways via MMP-dependent heparin-binding EGF liberation and EGFR activation (Smith et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Matrix metalloprotease-9 induces transforming growth factor-β1 production in airway epithelium via activation of epidermal growth factor receptors

Perng

Chang

et al. 2011

Life Sciences

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“…[33][34][35] Mice lacking EGFR, ErbB2, or heparin-binding (HB)-EGF all develop cardiac hypertrophy and cardiomyopathy, whereas a subset of patients treated for EGFR-positive breast cancer with the ErbB2 antagonist Herceptin developed dilated cardiomyopathy. Ang II has been shown to transactivate the EGFR in isolated cardiomyocytes 36 and whole hearts, the latter study suggesting that ADAM12 was responsible for HB-EGF shedding and subsequent cellular hypertrophy.…”

Section: Transactivation Of Egf Receptors: a Common Pathway For Gpcr-mentioning

confidence: 99%

“…Although most studies to date have focused on HB-EGF, at least 5 of the 13 known EGF-like ligands, HB-EGF, TGF ␣, AR, betacellulin, and epiregulin, comprising both ErbB1 and ErbB4 ligands, can undergo regulated shedding. 59 Because each ligand binds a discrete subset of ErbB receptors and is, thus, capable of forming ErbB homodimers and heterodimers with different response profiles, 35 the possibility exists that cell type-specific shedding of different ligands determines the outcome of ErbB transactivation in different contexts. 60 Another confounding observation is that Ang II reportedly stimulates formation of a physical complex between the AT 1 R and EGFR, suggesting that transactivation may occur over short distances in the context of signaling microdomains or multiprotein signaling complexes that could serve to modify the signal output.…”

Section: Transactivation Of Egf Receptors: a Common Pathway For Gpcr-mentioning

confidence: 99%

Signal Switching, Crosstalk, and Arrestin Scaffolds

Smith

Luttrell

2006

Hypertension

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H ormone agonists, including angiotensin II (Ang II), norepinephrine, urotensin II, endothelin-1, vasopressin, and serotonin, mediate a plethora of physiological and pathological cardiovascular events via their cognate 7 membrane-spanning G protein-coupled receptors (GPCRs). On ligand binding, GPCRs undergo conformational changes that enable the activation and dissociation of heterotrimeric guanine nucleotide binding proteins (G proteins) and trigger a range of intracellular second messenger signaling cascades. Because of the immediacy of second messenger generation, GPCRs are able to acutely regulate cardiovascular events such as heart rate, contractile force, and systemic vascular resistance. Compelling evidence for GPCR control in the vasculature comes from both transgenic studies and clinical findings. For example, ␤-adrenergic receptor blockers and inhibitors of the synthesis and binding of Ang II are proven antihypertensive therapeutics for humans. Furthermore, mice lacking RGS2, a regulatory protein that enhances the speed of GPCR signal termination, display marked hypertension, increased basal vascular tone, and hypersensitivity to vasoconstrictive agonists, 1 a phenotype that demonstrates the contribution of immediate GPCR-dependent signals, as well as the effect of GPCR dysregulation on cardiovascular homeostasis.The evidence that signals emanating from GPCRs also contribute to the chronic development of vascular disease is persuasive. Overexpression of the G␣q subunit in cardiomyocytes directly stimulates cardiac hypertrophy and decompensated heart failure, 2 whereas transgenic mice expressing an inhibitory fragment of G␣q exhibit reduced hypertrophy in response to pressure overload. 3 GPCR agonists like Ang II, endothelin-1, and norepinephrine, act directly on cardiomyocytes to stimulate hypertrophy. 4 Meanwhile, Ang II contributes to atherosclerosis via activation of vascular smooth muscle cell (VSMC) migration and hypertrophy; this occurs either directly, via the Ang II type 1 receptor (AT 1 R), or indirectly by stimulating endothelin-1 expression or activating inflammatory pathways. 5 Importantly, these pathological vascular effects require significant modulation of gene transcription, often via activation of growth-promoting mitogen-activated protein kinase (MAPK) cascades.A confounding issue in GPCR biology has been the incongruity between acute second messenger signals generated by ligand binding and longer-term changes in gene expression and cell growth. Indeed, studies over the past decade have demonstrated that GPCR signaling is more complicated than predicted by the ternary complex model of receptor-G protein-effector signaling. Receptor coupling specificity can be modified by phosphorylation, not only quantitatively in terms of desensitization, but also qualitatively via G protein "switching." Many, if not most, GPCRs engage in crosstalk with receptor tyrosine kinases (RTKs). Transactivation of epidermal growth factor (EGF) receptors allows GPCRs to initiate Ras-dependent signals that cont...

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Tackling the EGFR in pathological tissue remodelling

Cited by 27 publications

References 35 publications

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

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

Matrix metalloprotease-9 induces transforming growth factor-β1 production in airway epithelium via activation of epidermal growth factor receptors

Signal Switching, Crosstalk, and Arrestin Scaffolds

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