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

• Published in: Scientific reports Vol. 11; no. 1; p. 6160
• Main Authors: Rohwedder, Arndt, Knipp, Sabine, Roberts, Lee D., Ladbury, John E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337; 631/45; 631/535; 631/57; 631/57/2271; 631/80; Cell Membrane - metabolism; Corruption; Fibroblast growth factor receptor 2; GRB2 Adaptor Protein - metabolism; Grb2 protein; Growth factors; HEK293 Cells; Humanities and Social Sciences; Humans; Intracellular signalling; Ligands; Lipids; Membrane proteins; multidisciplinary; Protein Binding; Protein Domains; Protein interaction; Protein-tyrosine kinase receptors; Proteins; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Science; Science (multidisciplinary); Signal transduction
• DOI: 10.1038/s41598-021-85578-8
• ISSN: 2045-2322

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.