Role of EGFR in Adenosine A1 Receptor Signaling and Cardioprotection

Williams-Pritchard, Grant; Knight, M.; Hoe, L. See; Headrick, John P.; Peart, Jason Nigel John

doi:10.1016/j.hlc.2010.06.776

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“…GPCRs have been linked to EGFR transactivation in cardiac cells including the AT1R (Smith, Chan, Qian et al, 2011;Thomas, Brandenburger, Autelitano et al, 2002), adrenergic (Kim, Eckhart, Eguchi et al, 2002;Turner, 2003), muscarinic (Krieg, Qin, McIntosh et al, 2002;Miao, Bi, Zhao et al, 2015), adenosine (Williams-Pritchard, Knight, Hoe et al, 2011), endothelin (Clerk & Sugden, 1999;Kodama, Fukuda, Takahashi et al, 2002), bradykinin (Methner, Donat, Felix et al, 2009), opioid (Cao, Liu & Van Winkle, 2005;Förster, Kuno, Solenkova et al, 2007) and the protease activated receptor (Sabri, 2002). G proteindependent signalling in the heart has been studied for decades, revealing significant roles for Gq/11 in the increased production of protein synthesis and hypertrophic responses in the heart.…”

Section: Evidence For Egfr Transactivation In the Heartmentioning

confidence: 99%

“…A number of prominent GPCRs have been reported to transactivate the EGFR, including the adrenergic (Kim, Eckhart, Eguchi et al, 2002;Turner, 2003), dopamine (Yoon & Baik, 2013), bradykinin (Methner, Donat, Felix et al, 2009), vasopressin (Fuentes, Reyes, Sarmiento et al, 2008;Zhang, Wang, Cao et al, 2016) and adenosine receptors (Williams-Pritchard, Knight, Hoe et al, 2011), although the exact mechanisms remain unresolved. We next examined whether the BRET-based Grb2 recruitment assay could be used to screen multiple GPCRs and measure their capacity to transactivate the EGFR.…”

Section: Screening For Egfr Transactivation By Multiple Gpcrsmentioning

confidence: 99%

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New mechanisms of receptor crosstalk

O’Brien¹

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Dysregulation of the Renin Angiotensin System (RAS), and its cognate receptor, the angiotensin (AngII) type 1 receptor (AT1R), has been implicated in the pathogenesis of several cardiovascular disorders including hypertension, fibrosis, congestive heart failure and stroke. Despite the development of pharmacological agents that target the RAS, the persistent burden of cardiovascular disease remains. My PhD focuses on the AT1R, specifically its ability to 'crosstalk' and transactivate signalling pathways downstream of the Epidermal Growth Factor Receptors (EGFR). This paradigm of EGFR transactivation thereby enables the AT1R to potentially regulate cell growth, differentiation, apoptosis and promote cancerous cell growth. Part of ongoing work in the Thomas laboratory is to better understand the roll of previously identified novel proteins in AT1R-EGFR transactivation, including CHKA (Choline Kinase Alpha), BMX (non-receptor tyrosine kinase) and TRIO (Triple Functional Domain PTPRF Interacting). It is therefore the focus of my research to use molecular and cellular approaches to interrogate the mechanistic basis for EGFR transactivation and better define the relative role of these novel proteins in AT1R-EGFR signalling. Although it is of great interest to identify and characterise the molecular, temporal and spatial mechanisms of AT1R-EGFR transactivation, demonstrating EGFR transactivation directly, in live cells, and in real-time has been challenging. Typically, end-point assays (e.g., phospho-ERK1/2) are used as a surrogate readout of EGFR activation, however they are often downstream readouts and are not applicable to live cells. Herein, I report the use of a Bioluminescence Resonance Energy Transfer (BRET) based assay to report the recruitment of the EGFR adaptor protein, growth factor receptor-bound protein 2 (Grb2), association with the EGFR. In live HEK293 cells, both epidermal growth factor (EGF) and AngII stimulation produced sustained ligand-dependent recruitment of Grb2 to the EGFR. The BRET assay was applied to a variety of cell lines and also used to screen a panel of 19 GPCRs, with the AT1R and vasopressin receptor showing distinct EGFR transactivation. Additionally, HER2, a member of the EGFR family (also known as ErbB2) and preferred dimerisation partner of the EGFR, was also transactivated by the AT1R. Mechanistically, we observed that the AT1R-mediated ERK1/2 activation was completely dependent on Gq/11 as well as EGFR tyrosine kinase activity, whereas EGFR-Grb2 recruitment was independent of Gq/11 and only I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from coauthors for any jointly authored works included in the thesis.

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Section: Evidence For Egfr Transactivation In the Heartmentioning

confidence: 99%

Section: Screening For Egfr Transactivation By Multiple Gpcrsmentioning

confidence: 99%

New mechanisms of receptor crosstalk

O’Brien¹

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Role of EGFR in Adenosine A1 Receptor Signaling and Cardioprotection

Cited by 1 publication

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New mechanisms of receptor crosstalk

New mechanisms of receptor crosstalk

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