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

George, Amee J.; Purdue, Brooke W.; Gould, Cathryn M.; Thomas, D. Winton; Handoko, Yanny; Qian, Hongwei; Quaife-Ryan, Gregory A.; Morgan, Kylie A; Simpson, Kaylene J.; Thomas, Walter G.; Hannan, Ross D.

doi:10.1242/jcs.128280

Cited by 32 publications

(42 citation statements)

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“…Angiotensin II activates the angiotensin type 1 receptor (AT1R), which then transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth. Knockdown of Bmx was shown to attenuate tyrosine phosphorylation of the EGFR by angiotensin II stimulation in mammary epithelial cells, but Bmx did not have an effect on direct stimulation of the EGFR with EGF, indicating that Bmx functions between the activated AT1R and EGFR (21). Bmx also induces the tyrosine phosphorylation and DNA binding activity of STAT1, STAT3, and STAT5 (22).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

Holopainen

Räsänen

Anisimov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

Holopainen

Räsänen

Anisimov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Conversely, Zhang et al (2015) showed that the cardioprotective  opioid receptor transactivates the EGFR via PKC dependent ligand shedding, with -arrestin2 recruited to the distal EGFR (not the  opioid receptor). Finally, a recent functional siRNA screen in human epithelial cells has identified novel mediators of EGFR transactivation, including TRIO, BMX and CHKA (George et al, 2013b). Their knockdown impairs EGFR phosphorylation in response to GPCR agonism, but not direct activation with EGF, locating the proteins between the GPCR and EGFR.…”

Section: Mechanisms Of Egfr Transactivationmentioning

confidence: 99%

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

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“…Individual down regulation of TRIO, BMX or CHKA attenuated the activation of EGFR by Ang II, but not by the EGFR agonist EGF, suggesting that these factors are located upstream of EGFR and required for EGFR transactivation (George et al, 2013). These studies suggested that the pathway for GPCR to transactivate EGFR is much more complicated than that previously proposed.…”

Section: Potential Mechanisms For Erbb1 Transactivation By Ang Ii: Thmentioning

confidence: 81%

“…Indeed, our group has recently used functional genomics to perform a siRNA screen of AT 1 R-ErbB1 transactivation in a mammary epithelial cell line, and have identified a number of novel molecules involved in this process (George et al, 2013). It is also important to recognize the difficulties in characterizing systems that involve multiple molecular participants, and thus may have a high degree of redundancy.…”

Section: Discussionmentioning

confidence: 99%

“…Despite this controversy, these studies suggested that it is highly possible that there are more factors involved in transactivation that are yet to be discovered. Recently, a siRNA screen identified multiple new candidates such as TRIO, BMX and CHKA that may mediate the transactivation of EGFR by Ang II in a human mammary epithelial cell line (George et al, 2013).…”

Section: Potential Mechanisms For Erbb1 Transactivation By Ang Ii: Thmentioning

confidence: 99%

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Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

Wang¹

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ErbB receptors (ErbB1 -ErbB4) are a subfamily of tyrosine kinase receptors that regulate cell proliferation and differentiation. It has been proposed that the ErbB1 subtype is transactivated by Ang II to mediate cardiac hypertrophy. However, whether other ErbB receptors, in particular the abundant subtype ErbB4, are involved in this process is not known. ErbB4 has four isoforms due to alternative splicing, each of which might play a distinct role in regulating cell activity. However, the role of individual ErbB4 isoforms in hypertrophic signalling has not been investigated. In addition, ErbB4 activation is critical for cardiac development, cardiomyocyte survival in various rodent models of cardiovascular pathologies. However, the physiological role of ErbB4 in the adult heart remains poorly understood. The overall aim of my PhD project is to examine the role of the ErbB4 receptor in mediating hypertrophic growth of cardiomyocytes in vitro, and maintenance of the adult heart in vivo.To investigate the role of ErbB1, ErbB2 and ErbB4 in mediating hypertrophy, I inhibited individual ErbB receptors in primary neonatal rat ventricular cardiomyocytes using RNA interference or a pharmacological inhibitor (AG1478). Hypertrophy induced with Ang II (100 nM) or NRG1 (10 nM) was assessed by measuring the promoter activity of hypertrophic genes, ERK1/2 activation, and hypertrophic growth. The NRG1-induced hypertrophy was reduced by down-regulation of Following the studies above, I investigated whether the different ErbB4 isoforms had any functional differences in the cardiomyocytes. Irrespective of any changes in total ErbB4 mRNA levels, expression of the non-cleavable JM-b isoform was always predominant in adult heart in both physiological and pathological conditions. Although the cleavable isoform JM-a was detectable, it is not cleaved in cardiomyocytes. I replaced the endogenous ErbB4 with exogenous individual isoform in cardiomyocytes and found that all four isoforms of ErbB4 could mediate the NRG1-induced hypertrophic signalling. This suggests that the hypertrophy is triggered by a common feature of the four isoforms (ostensibly the kinase activity), and appears independent of isoformspecific features, such as the cleavable domain.To investigate the physiological function of ErbB4 in adult heart, we adopted the tamoxifeniii inducible αMHC-MerCreMer/loxP system to induce ErbB4 deletion from cardiomyocytes in the adult mouse. The expression of ErbB4 was reduced by ~ 90% at 10 days after tamoxifen treatment. Echocardiography revealed no differences in cardiac function (fractional shortening) betweenErbB4-conditional knockout (ErbB4-cKO) and control groups at 3-4 months after deletion of ErbB4. However, the heart weight was increased in ErbB4-cKO animals. Interestingly, there is no change in cardiac structure (cardiomyocyte size and cardiac fibrosis) or the expression of genes associated with pathological hypertrophy. This suggests that the cardiac hypertrophy observed following ErbB4 deletion may be physiological, a...

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

Cited by 32 publications

References 75 publications

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

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