Epidermal growth factor receptor association with β1-adrenergic receptor is mediated via its juxtamembrane domain.

Viren Patwa, Shuchi Guo, Rhonda L Carter, Lindsay Kraus, Jeanette Einspahr, David Teplitsky, Abdelkarim Sabri, Douglas G Tilley

Cellular signalling 2021 Feb

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β1-adrenergic receptor (β1AR)-mediated transactivation of epidermal growth factor receptor (EGFR) engages downstream signaling events that impact numerous cellular processes including growth and survival. While association of these receptors has been shown to occur basally and be important for relaying transactivation-specific intracellular events, the mechanism by which they do so is unclear and elucidation of which would aid in understanding the consequence of disrupting their interaction. Using fluorescence resonance energy transfer (FRET) and immunoprecipitation (IP) analyses, we evaluated the impact of C-terminal truncations of EGFR on its ability to associate with β1AR. While loss of the last 230 amino acid C-terminal phosphotyrosine-rich domain did not disrupt the ability of EGFR to associate with β1AR, truncation of the entire intracellular domain of EGFR resulted in almost complete loss of its interaction with β1AR, suggesting that either the kinase domain or juxtamembrane domain (JMD) may be required for this association. Treatment with the EGFR antagonist gefitinib did not prevent β1AR-EGFR association, however, treatment with a palmitoylated peptide encoding the first 20 amino acids of the JMD domain (JMD-A) disrupted β1AR-EGFR association over time and prevented β1AR-mediated ERK1/2 phosphorylation, both in general and specifically in association with EGFR. Conversely, neither a mutated JMD-A peptide nor a palmitoylated peptide fragment consisting of the subsequent 18 amino acids of the JMD domain (JMD-B) were capable of doing so. Altogether, the proximal region of the JMD of EGFR is responsible for its association with β1AR, and its disruption prevents β1AR-mediated transactivation, thus providing a new tool to study the functional consequences of disrupting β1AR-EGFR downstream signaling. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Viren Patwa, Shuchi Guo, Rhonda L Carter, Lindsay Kraus, Jeanette Einspahr, David Teplitsky, Abdelkarim Sabri, Douglas G Tilley. Epidermal growth factor receptor association with β1-adrenergic receptor is mediated via its juxtamembrane domain. Cellular signalling. 2021 Feb;78:109846