Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction

Abstract Receptor tyrosine kinases (RTKs) are highly regulated, single pass transmembrane proteins, fundamental to cellular function and survival. Aberrancies in regulation lead to corruption of signal transduction and a range of pathological outcomes. Although control mechanisms associated with the...

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Autores principales:	Arndt Rohwedder, Sabine Knipp, Lee D. Roberts, John E. Ladbury
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/da6ab08961324858bf419780f90c8fa2
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spelling	oai:doaj.org-article:da6ab08961324858bf419780f90c8fa22021-12-02T11:39:27ZComposition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction10.1038/s41598-021-85578-82045-2322https://doaj.org/article/da6ab08961324858bf419780f90c8fa22021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85578-8https://doaj.org/toc/2045-2322Abstract Receptor tyrosine kinases (RTKs) are highly regulated, single pass transmembrane proteins, fundamental to cellular function and survival. Aberrancies in regulation lead to corruption of signal transduction and a range of pathological outcomes. Although control mechanisms associated with the receptors and their ligands are well understood, little is known with respect to the impact of lipid/lipid and lipid/protein interactions in the proximal plasma membrane environment. Given that the transmembrane regions of RTKs change in response to extracellular ligand binding, the lipid interactions have important consequences in influencing signal transduction. Fibroblast growth factor receptor 2 (FGFR2) is a highly regulated RTK, including under basal conditions. Binding of the adaptor protein, growth factor receptor-bound protein 2 (GRB2) to FGFR2 prevents full activation and recruitment of downstream signalling effector proteins in the absence of extracellular stimulation. Here we demonstrate that the FGFR2-GRB2 complex is sustained in a defined lipid environment. Dissociation of GRB2 from this complex due to ligand binding, or reduced GRB2 expression, facilitates the dispersion of FGFR2 into detergent-resistant membrane (DRM) micro-domains. This modification of the plasma membrane proximal to FGFR2 provides a further regulatory checkpoint which controls receptor degradation, recycling and recruitment of intracellular signalling proteins.Arndt RohwedderSabine KnippLee D. RobertsJohn E. LadburyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arndt Rohwedder Sabine Knipp Lee D. Roberts John E. Ladbury Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
description	Abstract Receptor tyrosine kinases (RTKs) are highly regulated, single pass transmembrane proteins, fundamental to cellular function and survival. Aberrancies in regulation lead to corruption of signal transduction and a range of pathological outcomes. Although control mechanisms associated with the receptors and their ligands are well understood, little is known with respect to the impact of lipid/lipid and lipid/protein interactions in the proximal plasma membrane environment. Given that the transmembrane regions of RTKs change in response to extracellular ligand binding, the lipid interactions have important consequences in influencing signal transduction. Fibroblast growth factor receptor 2 (FGFR2) is a highly regulated RTK, including under basal conditions. Binding of the adaptor protein, growth factor receptor-bound protein 2 (GRB2) to FGFR2 prevents full activation and recruitment of downstream signalling effector proteins in the absence of extracellular stimulation. Here we demonstrate that the FGFR2-GRB2 complex is sustained in a defined lipid environment. Dissociation of GRB2 from this complex due to ligand binding, or reduced GRB2 expression, facilitates the dispersion of FGFR2 into detergent-resistant membrane (DRM) micro-domains. This modification of the plasma membrane proximal to FGFR2 provides a further regulatory checkpoint which controls receptor degradation, recycling and recruitment of intracellular signalling proteins.
format	article
author	Arndt Rohwedder Sabine Knipp Lee D. Roberts John E. Ladbury
author_facet	Arndt Rohwedder Sabine Knipp Lee D. Roberts John E. Ladbury
author_sort	Arndt Rohwedder
title	Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
title_short	Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
title_full	Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
title_fullStr	Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
title_full_unstemmed	Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
title_sort	composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/da6ab08961324858bf419780f90c8fa2
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Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction

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