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Complex Formation between VEGFR2 and the ?2-Adrenoceptor.

ABSTRACT: Vascular endothelial growth factor (VEGF) is an important mediator of endothelial cell proliferation and angiogenesis via its receptor VEGFR2. A common tumor associated with elevated VEGFR2 signaling is infantile hemangioma that is caused by a rapid proliferation of vascular endothelial cells. The current first-line treatment for infantile hemangioma is the ?-adrenoceptor antagonist, propranolol, although its mechanism of action is not understood. Here we have used bioluminescence resonance energy transfer and VEGFR2 genetically tagged with NanoLuc luciferase to demonstrate that oligomeric complexes involving VEGFR2 and the ?2-adrenoceptor can be generated in both cell membranes and intracellular endosomes. These complexes are induced by agonist treatment and retain their ability to couple to intracellular signaling proteins. Furthermore, coupling of ?2-adrenoceptor to ?-arrestin2 is prolonged by VEGFR2 activation. These data suggest that protein-protein interactions between VEGFR2, the ?2-adrenoceptor, and ?-arrestin2 may provide insight into their roles in health and disease.

SUBMITTER: Kilpatrick LE

PROVIDER: S-EPMC6593180 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Complex Formation between VEGFR2 and the β<sub>2</sub>-Adrenoceptor.

Kilpatrick Laura E LE Alcobia Diana C DC White Carl W CW Peach Chloe J CJ Glenn Jackie R JR Zimmerman Kris K Kondrashov Alexander A Pfleger Kevin D G KDG Ohana Rachel Friedman RF Robers Matthew B MB Wood Keith V KV Sloan Erica K EK Woolard Jeanette J Hill Stephen J SJ

Cell chemical biology 20190404 6

Vascular endothelial growth factor (VEGF) is an important mediator of endothelial cell proliferation and angiogenesis via its receptor VEGFR2. A common tumor associated with elevated VEGFR2 signaling is infantile hemangioma that is caused by a rapid proliferation of vascular endothelial cells. The current first-line treatment for infantile hemangioma is the β-adrenoceptor antagonist, propranolol, although its mechanism of action is not understood. Here we have used bioluminescence resonance ener ...[more]

PMID: 30956148

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Project description:Background and purposeStress-related catecholamines have a role in cancer and β-adrenoceptors; specifically, β2 -adrenoceptors have been identified as new targets in treating melanoma. Recently, β3 -adrenoceptors have shown a pleiotropic effect on melanoma micro-environment leading to cancer progression. However, the mechanisms by which β3 -adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub-population homeostasis. Understanding the mechanisms of cancer immune-tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β3 -adrenoceptors in immune-tolerance regulation.Experimental approachA mouse model of melanoma in which syngeneic B16-F10 cells were injected in C57BL-6 mice was used to evaluate the effect of β-adrenoceptor blockade on the number and activity of immune cell sub-populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β-blockers (propranolol and SR59230A) and specific β-adrenoceptor siRNAs targeting β2 - or β3 -adrenoceptors were used.Key resultsOnly β3 -, but not β2 -adrenoceptors, were up-regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub-populations including Treg, MDSC, and NK. SR59230A and β3 -adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub-populations in the tumour mass, blood, and spleen. SR59230A and β3 -adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes.Conclusions and implicationsOur data suggest that β3 -adrenoceptors are involved in immune-tolerance, which opens the way for new strategic therapies to overcome melanoma growth.Linked articlesThis article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

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Complex Formation between VEGFR2 and the ?2-Adrenoceptor.

Publications

Complex Formation between VEGFR2 and the β<sub>2</sub>-Adrenoceptor.

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