The role of EGFR in vascular AT1R signaling: From cellular mechanisms to systemic relevance

Gekle, Michael; Dubourg, Virginie; Schwerdt, Gerald; Benndorf, Ralf A.; Schreier, Barbara

doi:10.1016/j.bcp.2023.115837

Cited by 4 publications

(3 citation statements)

References 146 publications

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“…The EGFR is a member of receptor tyrosine kinases family, which plays a crucial role in vascular AT 1 R function, influencing signaling, promoting remodeling, contributing to inflammation, and participating in the pathogenesis of cardiovascular diseases 79,80 . Activation of AT 1 R induces transactivation of EGFR, subsequently influencing cellular growth, tissue remodeling, and cellular hypertrophy 80 . The crosstalk between AT 1 R and EGFR amplifies the signaling response, enhancing the biological effects of Ang II 81 .…”

Section: Angiotensin Receptor Heteromerizationmentioning

confidence: 99%

Unraveling the crosstalk between renin‐angiotensin system receptors

Gironacci,

Bruna‐Haupt

2024

Acta Physiologica

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The renin‐angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro‐inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang‐(1–7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G‐protein‐coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher‐order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.

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Section: Angiotensin Receptor Heteromerizationmentioning

confidence: 99%

Unraveling the crosstalk between renin‐angiotensin system receptors

Gironacci,

Bruna‐Haupt

2024

Acta Physiologica

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“…Furthermore, the AT 1 R is also capable of promoting signaling through other transmembrane receptors, such as the EGFR through β-arrestindependent and -independent mechanisms. [174][175][176] Food and Drug Administration approved reninangiotensin-aldosterone system inhibitors include direct renin inhibitors, ACEIs (angiotensin-converting enzyme inhibitors), AT 1 R antagonists (ARBs), and mineralocorticoid receptor antagonists. ACEIs and ARBs are central to the treatment of hypertension, HF with reduced ejection fraction, and chronic kidney disease.…”

Section: Type 1 Angiotensin II Receptormentioning

confidence: 99%

“…Furthermore, the AT 1 R is also capable of promoting signaling through other transmembrane receptors, such as the EGFR through β-arrestin-dependent and -independent mechanisms. 174–176…”

Section: Important Gpcr Targets In Cardiovascular Medicinementioning

confidence: 99%

G Protein-Coupled Receptors: A Century of Research and Discovery

Liu,

Anderson,

Rajagopal

et al. 2024

Circulation Research

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GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and β-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of β-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

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Direct GPCR-EGFR interaction enables synergistic membrane-to-nucleus information transfer

Gekle,

Eckenstaler,

Braun

et al. 2024

Cell. Mol. Life Sci.

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We addressed the heteromerization of the epidermal growth factor receptor (EGFR) with G-protein coupled receptors (GPCR) on the basis of angiotensin-II-receptor-subtype-1(AT1R)-EGFR interaction as proof-of-concept and show its functional relevance during synergistic nuclear information transfer, beyond ligand-dependent EGFR transactivation. Following in silico modelling, we generated EGFR-interaction deficient AT1R-mutants and compared them to AT1R-wildtype. Receptor interaction was assessed by co-immunoprecipitation (CoIP), Förster resonance energy transfer (FRET) and fluorescence-lifetime imaging microscopy (FLIM). Changes in cell morphology, ERK1/2-phosphorylation (ppERK1/2), serum response factor (SRF)-activation and cFOS protein expression were determined by digital high content microscopy at the single cell level. FRET, FLIM and CoIP confirmed the physical interaction of AT1R-wildtype with EGFR that was strongly reduced for the AT1R-mutants. Responsiveness of cells transfected with AT1R-WT or –mutants to angiotensin II or EGF was similar regarding changes in cell circularity, ppERK1/2 (direct and by ligand-dependent EGFR-transactivation), cFOS-expression and SRF-activity. By contrast, the EGFR-AT1R-synergism regarding these parameters was completely absent for in the interaction-deficient AT1R mutants. The results show that AT1R-EGFR heteromerisation enables AT1R-EGFR-synergism on downstream gene expression regulation, modulating the intensity and the temporal pattern of nuclear AT1R/EGFR-information transfer. Furthermore, remote EGFR transactivation, via ligand release or cytosolic tyrosine kinases, is not sufficient for the complete synergistic control of gene expression.

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The role of EGFR in vascular AT1R signaling: From cellular mechanisms to systemic relevance

Cited by 4 publications

References 146 publications

Unraveling the crosstalk between renin‐angiotensin system receptors

Unraveling the crosstalk between renin‐angiotensin system receptors

G Protein-Coupled Receptors: A Century of Research and Discovery

Direct GPCR-EGFR interaction enables synergistic membrane-to-nucleus information transfer

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