Receptor tyrosine kinase activation induces free fatty acid 4 receptor phosphorylation, β-arrestin interaction, and internalization

• Published in: European journal of pharmacology 2019-07, Vol.855, p.267-275
• Main Authors: Villegas-Comonfort, Sócrates, Guzmán-Silva, Alejandro, Romero-Ávila, M. Teresa, Takei, Yoshinori, Tsujimoto, Gozoh, Hirasawa, Akira, García-Sáinz, J. Adolfo
• Format: Article
• Language: English
• Subjects: beta-Arrestins - metabolism; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Activators - pharmacology; FFA4; GPR120; HEK293 Cells; Humans; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Phosphorylation - drug effects; Protein Binding - drug effects; Protein Transport - drug effects; Receptor internalization; Receptor phosphorylation; Receptor Protein-Tyrosine Kinases - metabolism; Receptor tyrosine kinase; Receptors, G-Protein-Coupled - metabolism; Time Factors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.05.018

FFA4 (Free Fatty Acid receptor 4, previously known as GPR120) is a G protein-coupled receptor that acts as a sensor of long-chain fatty acids, modulates metabolism, and whose dysfunction participates in endocrine disturbances. FFA4 is known to be phosphorylated and internalized in response to agonists and protein kinase C activation. In this paper report the modulation of this fatty acid receptor by activation of receptor tyrosine kinases. Cell-activation with growth factors (insulin, epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor) increases FFA4 phosphorylation in a time- and concentration-dependent fashion. This effect was blocked by inhibitors of protein kinase C and phosphoinositide 3-kinase, suggesting the involvement of these kinases in it. FFA4 phosphorylation did not alter agonist-induced FFA4 calcium signaling, but was associated with decreased ERK 1/2 phosphorylation. In addition, insulin, insulin-like growth factor-I, epidermal growth factor, and to a lesser extent, platelet-derived growth factor, induce receptor internalization. This action of insulin, insulin-like growth factor I, and epidermal growth factor was blocked by inhibitors of protein kinase C and phosphoinositide 3-kinase. Additionally, cell treatment with these growth factors induced FFA4-β-arrestin coimmunoprecipitation. Our results evidenced cross-talk between receptor tyrosine kinases and FFA4 and suggest roles of protein kinase C and phosphoinositide 3-kinase in such a functional interaction. [Display omitted]